Heterocyclic compound

ABSTRACT

The present invention relates to compound (I) or a salt thereof which has a RORγt inhibitory action. 
     
       
         
         
             
             
         
       
     
     wherein each symbol is as defined in the specification.

TECHNICAL FIELD

The present invention relates to a heterocyclic compound having an RORγtinhibitory action, a medicament containing the compound, and the like.

Background of the Invention

Th17 cell and inflammatory cytokine (IL-17A, IL-17F, etc.) producedthereby cause a decrease in QOL as a severe etiology cell and factoraccompanying enhancement of a systemic new immune response, in variousautoimmune disease such as inflammatory bowel disease (IBD), rheumatoidarthritis, multiple sclerosis or psoriasis. However, the existingtherapeutic drugs show only limited effects, and therefore, the earliestpossible development of a novel therapeutic drug has been desired.

Involvement of T cells, inter alia, Th17 cell and inflammatory cytokines(IL-17A, IL-17F, etc.) produced thereby, in the pathology of theseimmune disease has been drawing attention in recent years.

Moreover, it has been recently clarified that a Retinoid-related OrphanReceptor (ROR) γt, which is one of the orphan nuclear receptors, playsan important role in the differentiation of Th17 cells and production ofIL-17A/IL-17F. That is, it has been reported that RORγt is mainlyexpressed in Th17 cells and functions as a transcription factor ofIL-17A and IL-17F, as well as a master regulator of Th17 celldifferentiation.

Therefore, a medicament that inhibits the action of RORγt is expected toshow a treatment effect on various immune disease by suppressingdifferentiation and activation of Th17 cells.

Patent Document 1 reports the following compound represented by thegeneral formula:

P-M-M₁

whereinM is a 3- to 8-membered linear chain consisting of carbon atoms, 0-3carbonyl groups, 0-1 thiocarbonyl group, and 0-4 heteroatoms selectedfrom O, N and S(O)_(p),one of P and M₁ is -G, and the other is -A-B;G is a group represented by the formula (IIa) or formula

Ring D, including the two atoms of Ring E to which it is attached, is a5- or 6-membered ring consisting of carbon atoms and 0-3 heteroatomsselected from N, O and S(O)_(p);Ring D is substituted with 0-2 R or 0-2 carbonyl, and there are 0-3 ringdouble bonds;E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl andpyridazinyl, which is substituted with 1-3 R;A is selected from a C₃₋₁₀ carbocycle substituted with 0-2 R⁴, and a5-12-membered heterocycle consisting of carbon atoms and 1-4 heteroatomsselected from N, O and S(O)_(p), and substituted with 0-2 R⁴;B is X—Y—R^(4a) or the like;X is absent, —(CR²R^(2a))₁₋₄— or the like;Y is selected from a C₃₋₁₀ carboncycle and a 3-10-membered heterocycle;andR^(4a) is a C₁₋₆ alkyl substituted with 0-2 R^(4c), or the like,which has a Xa factor inhibitory action, and is useful for the treatmentof thromboembolism.

Patent Document 2 discloses, as a fused heterocyclic compound, acompound represented by the formula:

whereinR^(1A) is an optionally substituted hydrocarbon group or an optionallysubstituted hydrocarbon-oxy group,R^(2A) and R^(3A) are each independently a hydrogen atom, an optionallysubstituted hydrocarbon group or the like, orR^(2A) and R^(3A) in combination optionally form, together with thecarbon atoms which they are bonded to, an optionally substitutedhydrocarbon ring,R^(5A) is a hydrogen atom or a halogen atom,

Q′ is

wherein

-   -   [A¹] are the same or different and each is a methylene group        optionally substituted by C₁₋₆ alkyl group(s) optionally        substituted by hydroxy group(s) and the like, wherein the two        substituents bonded to the single carbon atom are optionally        combined to each other to form a hydrocarbon ring, and    -   n is an integer of 1 to 5, or the like, and    -   Ring B′ is a benzene ring optionally further having        substituent(s), or the like,    -   which has a RORγt inhibitory action, and is useful for the        treatment of inflammatory bowel disease (IBD) and the like.

Patent Document 3 discloses a compound represented by the formula:

whereinRing A is a C₃₋₁₀ carbocycle;L is a group selected from a bond, —CHR¹⁰CHR¹⁰—, —CR¹⁰═CR¹⁰— and —C≡C—;R¹⁰ is H, halogen, OH or C₁₋₄ alkyl;Q is selected from C, CH and N;

is an optional bond; provided that when Q is N, then the optional bondis absent;Ring B is a 5- to 6-membered heterocycle containing heteroatoms selectedfrom N, NR⁶, O and S(O)_(p), and substituted by 0-3 R⁵;optionally, Ring B is further fused with phenyl substituted with 0-2 R⁵or a 5- to 6-membered aromatic heterocycle containing 1 to 2 heteroatomsselected from N, NR⁶, O and S(O)_(p), and substituted with 0-2 R⁵;R¹ are each independently H, halo, C₁₋₂ alkyl, —O(C₁₋₄ alkyl), CN,—CH₂NH₂ or —C(═NH)NH₂;R² is H, halo, CN, OH, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, CO(C₁₋₄ alkyl), CONH₂, CO₂H, and, a 5- to 7-memberedheterocycle containing 1 to 4 heteroatoms selected from N, NH, N(C₁₋₄alkyl), O and S(O)_(p), and substituted with 1-2 R^(2a); andR³ is a C₁₋₆ alkyl group substituted with 1-3 R^(3a), a C₃₋₁₀carboncycle substituted with 1-3 R³, or a 5- to 10-membered heterocyclecontaining 1 to 4 heteroatoms selected from N, NR⁷, O and S(O)_(p), andsubstituted with 1-3 R^(3a),which is a Factor XIIa, and is useful for the treatment ofthromboembolism and inflammatory disease.

Patent Document 4 discloses a compound represented by the formula:

whereinA¹ is CR^(A1) wherein R^(A1) is a hydrogen atom or a substituent, or anitrogen atom,A² is CR^(A2) wherein R^(A2) is a hydrogen atom or a substituent, or anitrogen atom,A³ is CR^(A3) wherein R^(A3) is a hydrogen atom or a substituent, or anitrogen atom, or,provided that when A² is CR^(A2) wherein R^(A2) is a substituent, andA³ is CR^(A3) wherein R^(A3) is a substituent, then R^(A2) and R^(A3) incombination optionally form, together with the carbon atoms which theyare bonded to, a carbocycle or a heterocycle,R¹ is an optionally substituted carbocyclic group or the like,R² is a hydrogen atom or a substituent,one of R³ or R⁴ is an optionally substituted carbocyclic group, anoptionally substituted aromatic nitrogen-containing heterocyclic groupor an optionally substituted fused non-aromatic heterocyclic group, andthe other is a hydrogen atom or a substituent,R⁵ is a hydrogen atom or a substituent, andR⁹ is a hydrogen atom or a hydroxy group, provided that when R⁹ is ahydroxy group, then A¹, A² and A³ are CR^(A1), CR^(A2) and CR^(A3),respectively.

Patent Document 5 discloses a compound represented by the formula:

whereinR¹ is C₁₋₂ alkyl, halogen or CF₃;R² is H, Cl, F or methyl;R³ is H, methyl;R⁴ is H, C₁₋₆ alkyl or benzyl optionally substituted by CF₃;R⁵ is methyl, nitro, halogen, CN, CF₃ or —C(O)OCH₂CH₃;R⁶ is Cl, F or CF₃; andm is 0 or 1,as a non-steroidal compound which is an androgen receptor modulator.

DOCUMENT LIST Patent Document [Patent Document 1] WO 2004/108892 [PatentDocument 2] WO 2013/042782 [Patent Document 3] WO 2013/055984 [PatentDocument 4] WO 2013/100027 [Patent Document 5] WO 2008/121602 SUMMARY OFTHE INVENTION Problems to be Solved by the Invention

The present invention aims to provide a compound having a superior RORγtinhibitory action, and useful as an agent for the prophylaxis ortreatment of psoriasis, inflammatory bowel disease (IBD), ulcerativecolitis (UC), Crohn's disease (CD), rheumatoid arthritis, multiplesclerosis, uveitis, asthma, ankylopoietic spondylarthritis, systemiclupus erythematosus (SLE) and the like.

Means of Solving the Problems

The present inventors have found that a compound represented by thefollowing formula (I) (including a compound represented by the formula(Ia)) or a salt thereof has a superior RORγt inhibitory action based onthe specific chemical structure thereof and affords superior efficacy asan agent for the prophylaxis or treatment of psoriasis, inflammatorybowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD),rheumatoid arthritis, multiple sclerosis, uveitis, asthma, ankylopoieticspondylarthritis, systemic lupus erythematosus (SLE) and the like. Thepresent inventors have conducted intensive studies based on the findingand completed the present invention.

Accordingly, the present invention relates to the followings.

[1] A compound represented by the following formula (I):

wherein

Ring A is an optionally further substituted 6-membered aromatic ring,

R¹ is

(1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))wherein Q is a carbon atom, a silicon atom or a germanium atom, andR^(1a), R^(1b) and R^(1c) are each independently a substituent, orR^(1a) and R^(1b) in combination optionally form, together with theadjacent Q, an optionally further substituted ring, and R^(1c) isoptionally bonded to one substituent for Ring A to form an optionallyfurther substituted ring,(2) a neo-pentyl group, or(3) a trimethylsilylmethyl group,

R¹¹ is —CR¹²R^(12′)—R^(12″), —C(═O)—R⁴ or —SO₂—R¹³,

R¹², R^(12′) and R^(12″) are each independently a hydrogen atom, ahalogen atom, a cyano group, a nitro group, an optionally substitutedC₁₋₆ alkyl group, an optionally substituted C₂₋₆ alkenyl group, anoptionally substituted C₂₋₆ alkynyl group, an optionally substitutedheterocyclic group or an optionally substituted thiocarbamoyl group,

R⁴ is an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted C₂₋₆alkenyl group, an optionally substituted C₂₋₆ alkynylgroup, an optionally substituted heterocyclic group, an acyl group, anoptionally substituted amino group, an optionally substituted carbamoylgroup, an optionally substituted thiocarbamoyl group, an optionallysubstituted sulfamoyl group, an optionally substituted hydroxy group, anoptionally substituted sulfanyl(SH) group or an optionally substitutedsilyl group,

wherein the “C₁₋₆ alkyl group”, the “C₂₋₆ alkenyl group” and the “C₂₋₆alkynyl group” of the “optionally substituted C₁₋₆ alkyl group”, the“optionally substituted C₂₋₆ alkenyl group” and the “optionallysubstituted C₂₋₆ alkynyl group” for R⁴ are each optionally substitutedby 1 to 5 substituents selected from (1) a halogen atom, (2) a nitrogroup, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) aC₁₋₆ alkoxy group optionally substituted by substituent(s) selected froma halogen atom and a carboxy group, (7) a C₆₋₁₄ aryloxy group, (8) aC₇₋₁₆ aralkyloxy group, (9) a 5- to 14-membered aromatic heterocyclyloxygroup, (10) a 3- to 14-membered non-aromatic heterocyclyloxy group, (11)a C₁₋₆ alkyl-carbonyloxy group, (12) a C₆₋₁₄ aryl-carbonyloxy group,(13) a C₁₋₆ alkoxy-carbonyloxy group, (14) a mono- or di-C₁₋₆alkyl-carbamoyloxy group, (15) a C₆₋₁₄ aryl-carbamoyloxy group, (16) a5- to 14-membered aromatic heterocyclylcarbonyloxy group, (17) a 3- to14-membered non-aromatic heterocyclylcarbonyloxy group, (18) anoptionally halogenated C₁₋₆ alkylsulfonyloxy group, (19) a C₆₋₁₄arylsulfonyloxy group optionally substituted by C₁₋₆ alkyl group(s),(20) an optionally halogenated C₁₋₆ alkylthio group, (21) a 5- to14-membered aromatic heterocyclic group optionally substituted bysubstituent(s) selected from a hydroxy group, a C₁₋₆ alkyl group, a C₁₋₆alkoxy group and a carboxy group, (22) a 3- to 14-membered non-aromaticheterocyclic group optionally substituted by substituent(s) selectedfrom an oxo group and a C₁₋₆ alkyl group, (23) a formyl group, (24) acarboxy group, (25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,(26) a C₆₋₁₄ aryl-carbonyl group, (27) a 5- to 14-membered aromaticheterocyclylcarbonyl group, (28) a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, (29) a C₁₋₆ alkoxy-carbonyl group, (30) aC₆₋₁₄ aryloxy-carbonyl group, (31) a C₇₋₁₆ aralkyloxy-carbonyl group,(32) a carbamoyl group, (33) a thiocarbamoyl group, (34) a mono- ordi-C₁₋₆ alkyl-carbamoyl group, (35) a C₆₋₁₄ aryl-carbamoyl group, (36) a5- to 14-membered aromatic heterocyclylcarbamoyl group, (37) a 3- to14-membered non-aromatic heterocyclylcarbamoyl group, (38) an optionallyhalogenated C₁₋₆ alkylsulfonyl group, (39) a C₆₋₁₄ arylsulfonyl group,(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group, (41) anoptionally halogenated C₁₋₆ alkylsulfinyl group, (42) a C₆₋₁₄arylsulfinyl group, (43) a 5- to 14-membered aromaticheterocyclylsulfinyl group, (44) an amino group, (45) a mono- or di-C₁₋₆alkylamino group (the C₁₋₆ alkyl is optionally substituted by carboxygroup(s)), (46) a mono- or di-C₆₋₁₄ arylamino group, (47) a 5- to14-membered aromatic heterocyclylamino group, (48) a C₇₋₁₆ aralkylaminogroup, (49) a formylamino group, (50) a C₁₋₆ alkyl-carbonylamino group,(51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group, (52) a C₆₋₁₄aryl-carbonylamino group, (53) a C₁₋₆ alkoxy-carbonylamino group, (54) aC₇₋₁₆ aralkyloxy-carbonylamino group, (55) a C₁₋₆ alkylsulfonylaminogroup, (56) a C₆₋₁₄ arylsulfonylamino group optionally substituted byC₁₋₆ alkyl group(s), (57) an optionally halogenated C₁₋₆ alkyl group,(58) a C₂₋₆ alkenyl group, and (59) a C₂₋₆ alkynyl group,

R¹³ is a substituent,

Ring B is a benzene ring, a pyridine ring or a dihydropyridine ring,each of which is optionally further substituted,

the partial structure represented by the formula:

is CR^(5a)═CR⁶, CR^(5b)═N or C(═O)—NR⁷,

R^(5a) and R^(5b) are each independently an optionally substituted alkylgroup, an optionally substituted alkoxy group, an optionally substitutedalkylsulfonyl group, a cyano group, an optionally substituted cyclicamino group or an oxetan-3-yloxy group, and

R⁶ and R⁷ are each independently a hydrogen atom or a substituent, or

the substituent that Ring B optionally further has and R^(5a) or R^(5b)in combination optionally form Ring D, wherein Ring D is a 5- or6-membered oxygen-containing heterocycle containing 1 to 2 oxygen atomsas heteroatoms in addition to carbon atoms, and is fused at the ringforming position, or

R^(5a) and R⁶ in combination optionally form Ring D′, wherein Ring D′ isa 5- or 6-membered oxygen-containing heterocycle containing 1 to 2oxygen atoms as heteroatoms in addition to carbon atoms, and is fused atthe ring forming position,

Y is an optionally substituted methylene group or an oxygen atom, and

W is an optionally substituted C₁₋₂ alkylene group, or a salt thereof(hereinafter sometimes to be referred to as compound (I)).

[2] The compound or salt of the above-mentioned [1], wherein R¹ is atrimethylsilyl group, an ethyldimethylsilyl group or an optionallysubstituted tert-butyl group, or a group represented by the formula:—C(R^(1a))(R^(1b))(R^(1c)) wherein R^(1a) and R^(1b) are eachindependently a substituent, or R^(1a) and R^(1b) in combinationoptionally form, together with the adjacent carbon atom, an optionallyfurther substituted ring, and R^(1c) is bonded to one substituent forRing A to form an optionally further substituted ring.[3] The compound or salt of the above-mentioned [1], wherein Ring A is abenzene ring optionally further substituted by a halogen atom or a cyanogroup.[4] The compound or salt of the above-mentioned [1], wherein R⁴ is (1) aC₁₋₆ alkyl group optionally substituted by 1 to 3 substituents selectedfrom (a) a halogen atom, (b) a cyano group, (c) a hydroxy group, (d) a5- to 6-membered monocyclic aromatic heterocyclic group, (e) a 4- to6-membered monocyclic non-aromatic heterocyclic group, and (f) a carboxygroup, or (2) an optionally substituted heterocyclic group.[5] The compound or salt of the above-mentioned [1], wherein Ring D′ isa dioxole ring.[6] The compound or salt of the above-mentioned [1], wherein Y and W areboth methylene groups.[7] The compound or salt of the above-mentioned [1], wherein R^(1a) is(1) an optionally substituted C₁₋₆ alkyl group, (2) an optionallysubstituted C₁₋₆ alkoxy group, or (3) an optionally substituted C₁₋₆alkylsulfonyl group.[8] The compound or salt of the above-mentioned [1], wherein R^(5b) is(1) an optionally substituted C₁₋₄ alkoxy group, or (2) an optionallysubstituted C₁₋₄ alkyl group.[9] The compound or salt of the above-mentioned [1], wherein R⁶ is ahydrogen atom.[10] The compound or salt of the above-mentioned [1], wherein Ring B isa benzene ring or a pyridine ring, each of which is optionally furthersubstituted.[11]5-((5R)-5-((7-Fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-oxopentanoicacid or a salt thereof.[12](1-(((6R)-6-((3,5-Difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-8,9-dihydro[1,3]dioxolo[4,5-f]isoquinolin-7(6H)-yl)carbonyl)azetidin-3-yl)aceticacid or a salt thereof.[13](1-(((5R)-5-((3,5-Difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)azetidin-3-yl)aceticacid or a salt thereof.[14] A medicament comprising the compound or salt of the above-mentioned[1].[15] The medicament of the above-mentioned [14], which is a RORγtinhibitor.[16] The medicament of the above-mentioned [14], which is an agent forthe prophylaxis or treatment of psoriasis, inflammatory bowel disease(IBD), ulcerative colitis (UC), Crohn's disease (CD), rheumatoidarthritis, multiple sclerosis, uveitis, asthma, ankylopoieticspondylarthritis or systemic lupus erythematosus (SLE).[17] A method of inhibiting RORγt, which comprises administering aneffective amount of the compound or salt of the above-mentioned [1] to amammal.[18] A method for the prophylaxis or treatment of psoriasis,inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn'sdisease (CD), rheumatoid arthritis, multiple sclerosis, uveitis, asthma,ankylopoietic spondylarthritis or systemic lupus erythematosus (SLE),which comprises administering an effective amount of the compound orsalt of the above-mentioned [1] to a mammal.[19] Use of the compound or salt of the above-mentioned [1] for theproduction of an agent for the prophylaxis or treatment of psoriasis,inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn'sdisease (CD), rheumatoid arthritis, multiple sclerosis, uveitis, asthma,ankylopoietic spondylarthritis or systemic lupus erythematosus (SLE).[20] The compound or salt of the above-mentioned [1] for use in theprophylaxis or treatment of psoriasis, inflammatory bowel disease (IBD),ulcerative colitis (UC), Crohn's disease (CD), rheumatoid arthritis,multiple sclerosis, uveitis, asthma, ankylopoietic spondylarthritis orsystemic lupus erythematosus (SLE).[1a] A compound represented by the formula (Ia):

wherein

Ring A is an optionally further substituted 6-membered aromatic ring,

R¹ is

(1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))wherein Q is a carbon atom, a silicon atom or a germanium atom, andR^(1a), R^(1b) and R^(1c) are each independently a substituent, orR^(1a) and R^(1b) in combination optionally form, together with theadjacent Q, an optionally further substituted ring, and R^(1c) isoptionally bonded to one substituent for Ring A to form an optionallyfurther substituted ring,(2) a neo-pentyl group, or(3) a trimethylsilylmethyl group,

R⁴ is a halogen atom, a cyano group, a nitro group, an optionallysubstituted C₁₋₆ alkyl group, an optionally substituted C₂₋₆ alkenylgroup, an optionally substituted C₂₋₆ alkynyl group, an optionallysubstituted heterocyclic group, an acyl group, an optionally substitutedamino group, an optionally substituted carbamoyl group, an optionallysubstituted thiocarbamoyl group, an optionally substituted sulfamoylgroup, an optionally substituted hydroxy group, an optionallysubstituted sulfanyl(SH) group or an optionally substituted silyl group,

wherein the “optionally substituted C₁₋₆ alkyl group”, the “optionallysubstituted C₂₋₆ alkenyl group” and the “optionally substituted C₂₋₆alkynyl group” for R⁴ are each optionally substituted by 1 to 5substituents selected from (1) a halogen atom, (2) a nitro group, (3) acyano group, (4) an oxo group, (5) a hydroxy group, (6) an optionallyhalogenated C₁₋₆ alkoxy group, (7) a C₆₋₁₄ aryloxy group, (8) a C₇₋₁₆aralkyloxy group, (9) a 5- to 14-membered aromatic heterocyclyloxygroup, (10) a 3- to 14-membered non-aromatic heterocyclyloxy group, (11)a C₁₋₆ alkyl-carbonyloxy group, (12) a C₆₋₁₄ aryl-carbonyloxy group,(13) a C₁₋₆ alkoxy-carbonyloxy group, (14) a mono- or di-C₁₋₆alkyl-carbamoyloxy group, (15) a C₆₋₁₄ aryl-carbamoyloxy group, (16) a5- to 14-membered aromatic heterocyclylcarbonyloxy group, (17) a 3- to14-membered non-aromatic heterocyclylcarbonyloxy group, (18) anoptionally halogenated C₁₋₆ alkylsulfonyloxy group, (19) a C_(A-14)arylsulfonyloxy group optionally substituted by C₁₋₆ alkyl group(s),(20) an optionally halogenated C₁₋₆ alkylthio group, (21) a 5- to14-membered aromatic heterocyclic group, (22) a 3- to 14-memberednon-aromatic heterocyclic group, (23) a formyl group, (24) a carboxygroup, (25) an optionally halogenated C₁₋₆ alkyl-carbonyl group, (26) aC₆₋₁₄ aryl-carbonyl group, (27) a 5- to 14-membered aromaticheterocyclylcarbonyl group, (28) a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, (29) a C₁₋₆ alkoxy-carbonyl group, (30) aC₆₋₁₄ aryloxy-carbonyl group, (31) a C₇₋₁₆ aralkyloxy-carbonyl group,(32) a carbamoyl group, (33) a thiocarbamoyl group, (34) a mono- ordi-C₁₋₆ alkyl-carbamoyl group, (35) a C₆₋₁₄ aryl-carbamoyl group, (36) a5- to 14-membered aromatic heterocyclylcarbamoyl group, (37) a 3- to14-membered non-aromatic heterocyclylcarbamoyl group, (38) an optionallyhalogenated C₁₋₆ alkylsulfonyl group, (39) a C₆₋₁₄ arylsulfonyl group,(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group, (41) anoptionally halogenated C₁₋₆ alkylsulfinyl group, (42) a C₆₋₁₄arylsulfinyl group, (43) a 5- to 14-membered aromaticheterocyclylsulfinyl group, (44) an amino group, (45) a mono- or di-C₁₋₆alkylamino group, (46) a mono- or di-C₆₋₁₄ arylamino group, (47) a 5- to14-membered aromatic heterocyclylamino group, (48) a C₇₋₁₆ aralkylaminogroup, (49) a formylamino group, (50) a C₁₋₆ alkyl-carbonylamino group,(51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group, (52) a C₆₋₁₄aryl-carbonylamino group, (53) a C₁₋₆ alkoxy-carbonylamino group, (54) aC₇₋₁₆ aralkyloxy-carbonylamino group, (55) a C₁₋₆ alkylsulfonylaminogroup, (56) a C₆₋₁₄ arylsulfonylamino group optionally substituted byC₁₋₆ alkyl group(s), (57) an optionally halogenated C₁₋₆ alkyl group,(58) a C₂₋₆ alkenyl group, and (59) a C₂₋₆ alkynyl group,

Ring B is a benzene ring, a pyridine ring or a dihydropyridine ring,each of which is optionally further substituted,

the partial structure represented by the formula:

is CR^(5a)═CR⁶, CR^(5b)═N or C(═O)—NR⁷,

-   -   R^(5a) and R^(5b) are each independently an optionally        substituted alkyl group or an optionally substituted alkoxy        group,    -   R⁶ and R⁷ are each independently a hydrogen atom or a        substituent,        -   Y is an optionally substituted methylene group or an oxygen            atom, and        -   W is an optionally substituted C₁₋₂ alkylene group, or a            salt thereof (hereinafter sometimes to be referred to as            compound (Ia)).            [2a] A compound represented by the formula (Ia):

wherein

Ring A is an optionally further substituted 6-membered aromatic ring,

R¹ is a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))wherein Q is a carbon atom or a silicon atom, and R^(1a), R^(1b) andR^(1c) are each independently a substituent, or R^(1a) and R^(1b) incombination optionally form, together with the adjacent Q, an optionallyfurther substituted ring, and R^(1c) is optionally bonded to onesubstituent for Ring A to form an optionally further substituted ring,or neo-pentyl group,

R⁴ is a halogen atom, a cyano group, a nitro group, an optionallysubstituted C₁₋₆ alkyl group, an optionally substituted C₂₋₆ alkenylgroup, an optionally substituted C₂₋₆ alkynyl group, an optionallysubstituted heterocyclic group, an acyl group, an optionally substitutedamino group, an optionally substituted carbamoyl group, an optionallysubstituted thiocarbamoyl group, an optionally substituted sulfamoylgroup, an optionally substituted hydroxy group, an optionallysubstituted sulfanyl(SH) group or an optionally substituted silyl group,

wherein the “optionally substituted C₁₋₆ alkyl group”, the “optionallysubstituted C₂₋₆ alkenyl group” and the “optionally substituted C₂₋₆alkynyl group” for R⁴ are each optionally substituted by 1 to 5substituents selected from (1) a halogen atom, (2) a nitro group, (3) acyano group, (4) an oxo group, (5) a hydroxy group, (6) an optionallyhalogenated C₁₋₆ alkoxy group, (7) a C₆₋₁₄ aryloxy group, (8) a C₇₋₁₆aralkyloxy group, (9) a 5- to 14-membered aromatic heterocyclyloxygroup, (10) a 3- to 14-membered non-aromatic heterocyclyloxy group, (11)a C₁₋₆ alkyl-carbonyloxy group, (12) a C₆₋₁₄ aryl-carbonyloxy group,(13) a C₁₋₆ alkoxy-carbonyloxy group, (14) a mono- or di-C₁₋₆alkyl-carbamoyloxy group, (15) a C₆₋₁₄ aryl-carbamoyloxy group, (16) a5- to 14-membered aromatic heterocyclylcarbonyloxy group, (17) a 3- to14-membered non-aromatic heterocyclylcarbonyloxy group, (18) anoptionally halogenated C₁₋₆ alkylsulfonyloxy group, (19) a C₆₋₁₄arylsulfonyloxy group optionally substituted by C₁₋₆ alkyl group(s),(20) an optionally halogenated C₁₋₆ alkylthio group, (21) a 5- to14-membered aromatic heterocyclic group, (22) a 3- to 14-memberednon-aromatic heterocyclic group, (23) a formyl group, (24) a carboxygroup, (25) an optionally halogenated C₁₋₆ alkyl-carbonyl group, (26) aC₆₋₁₄ aryl-carbonyl group, (27) a 5- to 14-membered aromaticheterocyclylcarbonyl group, (28) a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, (29) a C₁₋₆ alkoxy-carbonyl group, (30) aC₆₋₁₄ aryloxy-carbonyl group, (31) a C₇₋₁₆ aralkyloxy-carbonyl group,(32) a carbamoyl group, (33) a thiocarbamoyl group, (34) a mono- ordi-C₁₋₆ alkyl-carbamoyl group, (35) a C₆₋₁₄ aryl-carbamoyl group, (36) a5- to 14-membered aromatic heterocyclylcarbamoyl group, (37) a 3- to14-membered non-aromatic heterocyclylcarbamoyl group, (38) an optionallyhalogenated C₁₋₆ alkylsulfonyl group, (39) a C₆₋₁₄ arylsulfonyl group,(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group, (41) anoptionally halogenated C₁₋₆ alkylsulfinyl group, (42) a C₆₋₁₄arylsulfinyl group, (43) a 5- to 14-membered aromaticheterocyclylsulfinyl group, (44) an amino group, (45) a mono- or di-C₁₋₆alkylamino group, (46) a mono- or di-C₆₋₁₄ arylamino group, (47) a 5- to14-membered aromatic heterocyclylamino group, (48) a C₇₋₁₆ aralkylaminogroup, (49) a formylamino group, (50) a C₁₋₆ alkyl-carbonylamino group,(51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group, (52) a C₆₋₁₄aryl-carbonylamino group, (53) a C₁₋₆ alkoxy-carbonylamino group, (54) aC₇₋₁₆ aralkyloxy-carbonylamino group, (55) a C₁₋₆ alkylsulfonylaminogroup, (56) a C₆₋₁₄ arylsulfonylamino group optionally substituted byC₁₋₆ alkyl group(s), (57) an optionally halogenated C₁₋₆ alkyl group,(58) a C₂₋₆ alkenyl group, and (59) a C₂₋₆ alkynyl group,

Ring B is a benzene ring, a pyridine ring or a dihydropyridine ring,each of which is optionally further substituted,

the partial structure represented by the formula:

is CR^(5a)═CR⁶, CR^(5b)═N or C(═O)—NR⁷,

-   -   R^(5a) and R^(5b) are each independently an optionally        substituted alkyl group or an optionally substituted alkoxy        group,    -   R⁶ and R⁷ are each independently a hydrogen atom or a        substituent,        -   Y is an optionally substituted methylene group or an oxygen            atom, and        -   W is an optionally substituted C₁₋₂ alkylene group, or a            salt thereof.

Effect of the Invention

The compound of the present invention has a superior RORγt inhibitoryaction, and useful as an agent for the prophylaxis or treatment ofpsoriasis, inflammatory bowel disease (IBD), ulcerative colitis (UC),Crohn's disease (CD), rheumatoid arthritis, multiple sclerosis, uveitis,asthma, ankylopoietic spondylarthritis, systemic lupus erythematosus(SLE) and the like.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is explained in detail in the following.

The definition of each substituent used in the present specification isdescribed in detail in the following. Unless otherwise specified, eachsubstituent has the following definition.

In the present specification, examples of the “halogen atom” includefluorine, chlorine, bromine and iodine.

In the present specification, examples of the “C₁₋₆ alkyl group” includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and2-ethylbutyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl group” include a C₁₋₆ alkyl group optionally having 1 to 7,preferably 1 to 5, a halogen atoms. Specific examples thereof includemethyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl,pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and6,6,6-trifluorohexyl.

In the present specification, examples of the “C₂₋₆ alkenyl group”include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and5-hexenyl.

In the present specification, examples of the “C₂₋₆ alkynyl group”include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkyl group”include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl and adamantyl.

In the present specification, examples of the “optionally halogenatedC₃₋₁₀ cycloalkyl group” include a C₃₋₁₀ cycloalkyl group optionallyhaving 1 to 7, preferably 1 to 5, a halogen atoms. Specific examplesthereof include cyclopropyl, 2,2-difluorocyclopropyl,2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

In the present specification, examples of the “C₂₋₁₀ cycloalkenyl group”include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl and cyclooctenyl.

In the present specification, examples of the “C₇₋₁₆ aryl group” includephenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

In the present specification, examples of the “C₇₋₁₆ aralkyl group”include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

In the present specification, examples of the “C₁₋₆ alkoxy group”include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkoxy group” include a C₁₋₆ alkoxy group optionally having 1 to 7,preferably 1 to 5, a halogen atoms. Specific examples thereof includemethoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “C₃₋₁₀ cycloalkyloxygroup” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

In the present specification, examples of the “C₁₋₆ alkylthio group”include methylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio, tert-butylthio, pentylthio and hexylthio.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylthio group” include a C₁₋₆ alkylthio group optionally having 1to 7, preferably 1 to 5, a halogen atoms. Specific examples thereofinclude methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio and hexylthio.

In the present specification, examples of the “C₁₋₆ alkyl-carbonylgroup” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl,pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl,hexanoyl and heptanoyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl-carbonyl group” include a C₁₋₆ alkyl-carbonyl groupoptionally having 1 to 7, preferably 1 to 5, a halogen atoms. Specificexamples thereof include acetyl, chloroacetyl, trifluoroacetyl,trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

In the present specification, examples of the “C₁₋₆ alkoxy-carbonylgroup” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl andhexyloxycarbonyl.

In the present specification, examples of the “C₆₋₁₄ aryl-carbonylgroup” include benzoyl, 1-naphthoyl and 2-naphthoyl.

In the present specification, examples of the “C₇₋₁₆ aralkyl-carbonylgroup” include phenylacetyl and phenylpropionyl.

In the present specification, examples of the “5- to 14-memberedaromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl,thenoyl and furoyl.

In the present specification, examples of the “3- to 14-memberednon-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl,piperidinylcarbonyl and pyrrolidinylcarbonyl.

In the present specification, examples of the “mono- or di-C₁₋₆alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

In the present specification, examples of the “mono- or di-C₇₋₁₆aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.

In the present specification, examples of the “C₁₋₆ alkylsulfonyl group”include methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl andtert-butylsulfonyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylsulfonyl group” include a C₁₋₆ alkylsulfonyl group optionallyhaving 1 to 7, preferably 1 to 5, a halogen atoms. Specific examplesthereof include methylsulfonyl, difluoromethylsulfonyl,trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl,pentylsulfonyl and hexylsulfonyl.

In the present specification, examples of the “C₆₋₁₄ arylsulfonyl group”include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

In the present specification, examples of the “substituent” include ahalogen atom, a cyano group, a nitro group, an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, an acylgroup, an optionally substituted amino group, an optionally substitutedcarbamoyl group, an optionally substituted thiocarbamoyl group, anoptionally substituted sulfamoyl group, an optionally substitutedhydroxy group, an optionally substituted sulfanyl (SH) group and anoptionally substituted silyl group.

In the present specification, examples of the “hydrocarbon group”(including “hydrocarbon group” of “optionally substituted hydrocarbongroup”) include a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₆₋₁₄aryl group and a C₇₋₁₆ aralkyl group.

In the present specification, examples of the “optionally substitutedhydrocarbon group” include a hydrocarbon group optionally havingsubstituent(s) selected from the following Substituent group A.

[Substituent Group A]

(1) a halogen atom,(2) a nitro group,(3) a cyano group,(4) an oxo group,(5) a hydroxy group,(6) an optionally halogenated C₁₋₆ alkoxy group,(7) a C₆₋₁₄ aryloxy group (e.g., phenoxy, naphthoxy),(8) a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy),(9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,pyridyloxy),(10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g.,morpholinyloxy, piperidinyloxy),(11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy),(12) a C₆₋₁₄ aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy,2-naphthoyloxy),(13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),(14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,diethylcarbamoyloxy),(15) a C₆₋₁₄ aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy,naphthylcarbamoyloxy),(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g.,nicotinoyloxy),(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group(e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),(18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group (e.g.,methylsulfonyloxy, trifluoromethylsulfonyloxy),(19) a C₆₋₁₄ arylsulfonyloxy group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy),(20) an optionally halogenated C₁₋₆ alkylthio group,(21) a 5- to 14-membered aromatic heterocyclic group,(22) a 3- to 14-membered non-aromatic heterocyclic group,(23) a formyl group,(24) a carboxy group,(25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,(26) a C₆₋₁₄ aryl-carbonyl group,(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,(29) a C₁₋₆ alkoxy-carbonyl group,(30) a C₆₋₁₄ aryloxy-carbonyl group (e.g., phenyloxycarbonyl,1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),(31) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl),(32) a carbamoyl group,(33) a thiocarbamoyl group,(34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,(35) a C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl),(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl, thienylcarbamoyl),(37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g.,morpholinylcarbamoyl, piperidinylcarbamoyl),(38) an optionally halogenated C₁₋₆ alkylsulfonyl group,(39) a C₆₋₁₄ arylsulfonyl group,(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g.,pyridylsulfonyl, thienylsulfonyl),(41) an optionally halogenated C₁₋₆ alkylsulfinyl group,(42) a C₆₋₁₄ arylsulfinyl group (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl),(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g.,pyridylsulfinyl, thienylsulfinyl),(44) an amino group,(45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino, ethylamino,propylamino, isopropylamino, butylamino, dimethylamino, diethylamino,dipropylamino, dibutylamino, N-ethyl-N-methylamino),(46) a mono- or di-C₆₋₁₄ arylamino group (e.g., phenylamino),(47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,pyridylamino),(48) a C₇₋₁₆ aralkylamino group (e.g., benzylamino),(49) a formylamino group,(50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,propanoylamino, butanoylamino),(51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl) an amino group (e.g.,N-acetyl-N-methylamino),(52) a C₆₋₁₄ aryl-carbonylamino group (e.g., phenylcarbonylamino,naphthylcarbonylamino),(53) a C₁₋₆ alkoxy-carbonylamino group (e.g., methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino,tert-butoxycarbonylamino),(54) a C₇₋₁₆ aralkyloxy-carbonylamino group (e.g.,benzyloxycarbonylamino),(55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,ethylsulfonylamino),(56) a C₆₋₁₄ arylsulfonylamino group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino),(57) an optionally halogenated C₁₋₆ alkyl group,(58) a C₂₋₆ alkenyl group,(59) a C₂₋₆ alkynyl group,(60) a C₃₋₁₀ cycloalkyl group,(61) a C₃₋₁₀ cycloalkenyl group, and(62) a C₆₋₁₄ aryl group.

The number of the above-mentioned substituents in the “optionallysubstituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to3. When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

In the present specification, examples of the “heterocyclic group”(including “heterocyclic group” of “optionally substituted heterocyclicgroup”) include (i) an aromatic heterocyclic group, (ii) a non-aromaticheterocyclic group and (iii) a 7- to 10-membered bridged heterocyclicgroup, each containing, as a ring-constituting atom besides carbon atom,1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and anoxygen atom.

In the present specification, examples of the “aromatic heterocyclicgroup” (including “5- to 14-membered aromatic heterocyclic group”)include a 5- to 14-membered (preferably 5- to 10-membered) aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “aromatic heterocyclic group” include 5- or6-membered monocyclic aromatic heterocyclic groups such as thienyl,furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and

8- to 14-membered fused polycyclic (preferably bi or tricyclic) aromaticheterocyclic groups such as benzothiophenyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl,thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl,thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl,pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl,pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl,isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl,f-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl and the like.

In the present specification, examples of the “non-aromatic heterocyclicgroup” (including “3- to 14-membered non-aromatic heterocyclic group”)include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “non-aromatic heterocyclic group” include 3-to 8-membered monocyclic non-aromatic heterocyclic groups such asaziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl,imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl,pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl,tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl,tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl,tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl,azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and thelike; and

9- to 14-membered fused polycyclic (preferably bi or tricyclic)non-aromatic heterocyclic groups such as dihydrobenzofuranyl,dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl,dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl,tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl,isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl,tetrahydroquinoxalinyl, tetrahydrophenanthridinyl,hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl,tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl,tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacrydinyl,tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl andthe like.

In the present specification, preferable examples of the “7- to10-membered bridged heterocyclic group” include quinuclidinyl and7-azabicyclo[2.2.1]heptanyl.

In the present specification, examples of the “nitrogen-containingheterocyclic group” include a “heterocyclic group” containing at leastone nitrogen atom as a ring-constituting atom.

In the present specification, examples of the “optionally substitutedheterocyclic group” include a heterocyclic group optionally havingsubstituent(s) selected from the above-mentioned Substituent group A.

The number of the substituents in the “optionally substitutedheterocyclic group” is, for example, 1 to 3. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

In the present specification, examples of the “acyl group” include aformyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group,a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group,each optionally having “1 or 2 substituents selected from a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀cycloalkenyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a 5- to14-membered aromatic heterocyclic group and a 3- to 14-memberednon-aromatic heterocyclic group, each of which optionally has 1 to 3substituents selected from a halogen atom, an optionally halogenatedC₁₋₆ alkoxy group, a hydroxy group, a nitro group, a cyano group, anamino group and a carbamoyl group”.

Examples of the “acyl group” also include a hydrocarbon-sulfonyl group,a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and aheterocyclylsulfinyl group.

Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bondedsulfonyl group, the heterocyclylsulfonyl group means a heterocyclicgroup-bonded sulfonyl group, the hydrocarbon-sulfinyl group means ahydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinylgroup means a heterocyclic group-bonded sulfinyl group.

Preferable examples of the “acyl group” include a formyl group, acarboxy group, a C₁₋₆ alkyl-carbonyl group, a C₂₋₆ alkenyl-carbonylgroup (e.g., crotonoyl), a C₃₋₁₀ cycloalkyl-carbonyl group (e.g.,cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,cycloheptanecarbonyl), a C₃₋₁₀ cycloalkenyl-carbonyl group (e.g.,2-cyclohexenecarbonyl), a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a C₆₋₁₄aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), aC₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl), a carbamoyl group, a mono- or di-C₁₋₆alkyl-carbamoyl group, a mono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g.,diallylcarbamoyl), a mono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbamoyl group (e.g.,phenylcarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-carbamoyl group, a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl), a thiocarbamoyl group, a mono- or di-C₁₋₆alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to14-membered aromatic heterocyclylthiocarbamoyl group (e.g.,pyridylthiocarbamoyl), a sulfino group, a C₁₋₆ alkylsulfinyl group(e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a C₁₋₆alkylsulfonyl group, a C₆₋₁₄ arylsulfonyl group, a phosphono group and amono- or di-C₁₋₆ alkylphosphono group (e.g., dimethylphosphono,diethylphosphono, diisopropylphosphono, dibutylphosphono).

In the present specification, examples of the “optionally substitutedamino group” include an amino group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from Substituentgroup A”.

Preferable examples of the optionally substituted amino group include anamino group, a mono- or di-(optionally halogenated C₁₋₆ alkyl) an aminogroup (e.g., methylamino, trifluoromethylamino, dimethylamino,ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C₂₋₆alkenylamino group (e.g., diallylamino), a mono- or di-C₃₋₁₀cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono-or di-C₆₋₁₄ arylamino group (e.g., phenylamino), a mono- or di-C₇₋₁₆aralkylamino group (e.g., benzylamino, dibenzylamino), a mono- ordi-(optionally halogenated C₁₋₆ alkyl)-carbonylamino group (e.g.,acetylamino, propionylamino), a mono- or di-C₆₋₁₄ aryl-carbonylaminogroup (e.g., benzoylamino), a mono- or di-C₇₋₁₆ aralkyl-carbonylaminogroup (e.g., benzylcarbonylamino), a mono- or di-5- to 14-memberedaromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino,isonicotinoylamino), a mono- or di-3- to 14-membered non-aromaticheterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), amono- or di-C₁₋₆ alkoxy-carbonylamino group (e.g.,tert-butoxycarbonylamino), a 5- to 14-membered aromaticheterocyclylamino group (e.g., pyridylamino), a carbamoylamino group, a(mono- or di-C₁₋₆ alkyl-carbamoyl) an amino group (e.g.,methylcarbamoylamino), a (mono- or di-C₇₋₁₆ aralkyl-carbamoyl) an aminogroup (e.g., benzylcarbamoylamino), a C₁₋₆ alkylsulfonylamino group(e.g., methylsulfonylamino, ethylsulfonylamino), a C₆₋₁₄arylsulfonylamino group (e.g., phenylsulfonylamino), a (C₁₋₆ alkyl)(C₁₋₆ alkyl-carbonyl) an amino group (e.g., N-acetyl-N-methylamino) anda (C₁₋₆ alkyl) (C₆₋₁₄ aryl-carbonyl) an amino group (e.g.,N-benzoyl-N-methylamino).

In the present specification, examples of the “optionally substitutedcarbamoyl group” include a carbamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromSubstituent group A”.

Preferable examples of the optionally substituted carbamoyl groupinclude a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group, amono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g., diallylcarbamoyl), amono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C₇₋₁₆aralkyl-carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbonyl-carbamoylgroup (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl).

In the present specification, examples of the “optionally substitutedthiocarbamoyl group” include a thiocarbamoyl group optionally having “1or 2 substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkylgroup, a C₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromSubstituent group A”.

Preferable examples of the optionally substituted thiocarbamoyl groupinclude a thiocarbamoyl group, a mono- or di-C₁₋₆ alkyl-thiocarbamoylgroup (e.g., methylthiocarbamoyl, ethylthiocarbamoyl,dimethylthiocarbamoyl, diethylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- ordi-C₁₋₆ alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl,propionylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-thiocarbamoylgroup (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromaticheterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl).

In the present specification, examples of the “optionally substitutedsulfamoyl group” include a sulfamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromSubstituent group A”.

Preferable examples of the optionally substituted sulfamoyl groupinclude a sulfamoyl group, a mono- or di-C₁₋₆ alkyl-sulfamoyl group(e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl,diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C₂₋₆alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C₃₋₁₀cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl,cyclohexylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-sulfamoyl group (e.g.,phenylsulfamoyl), a mono- or di-C₇₋₁₆ aralkyl-sulfamoyl group (e.g.,benzylsulfamoyl, phenethylsulfamoyl), a mono- or di-C₁₋₆,alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,propionylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-sulfamoyl group(e.g., benzoylsulfamoyl) and a 5- to 14-membered aromaticheterocyclylsulfamoyl group (e.g., pyridylsulfamoyl).

In the present specification, examples of the “optionally substitutedhydroxy group” include a hydroxyl group optionally having “a substituentselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a C₁₋₆alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₁₋₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from Substituentgroup A”.

Preferable examples of the optionally substituted hydroxy group includea hydroxy group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group (e.g.,allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C₃₋₁₀cycloalkyloxy group (e.g., cyclohexyloxy), a C₆₋₁₄ aryloxy group (e.g.,phenoxy, naphthyloxy), a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy,phenethyloxy), a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy,propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C₆₋₁₄aryl-carbonyloxy group (e.g., benzoyloxy), a C₇₋₁₆ aralkyl-carbonyloxygroup (e.g., benzylcarbonyloxy), a 5- to 14-membered aromaticheterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3- to 14-memberednon-aromatic heterocyclylcarbonyloxy group (e.g.,piperidinylcarbonyloxy), a C₁₋₆ alkoxy-carbonyloxy group (e.g.,tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclyloxygroup (e.g., pyridyloxy), a carbamoyloxy group, a C₁₋₆alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), a C₁₋₆aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), a C₁₋₆alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and aC₆₋₁₄ arylsulfonyloxy group (e.g., phenylsulfonyloxy).

In the present specification, examples of the “optionally substitutedsulfanyl group” include a sulfanyl group optionally having “asubstituent selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group and a 5- to14-membered aromatic heterocyclic group, each of which optionally has 1to 3 substituents selected from Substituent group A” and a halogenatedsulfanyl group.

Preferable examples of the optionally substituted sulfanyl group includea sulfanyl (—SH) group, a C₁₋₆ alkylthio group, a C₂₋₆ alkenylthio group(e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C₃₋₁₀cycloalkylthio group (e.g., cyclohexylthio), a C₆₋₁₄ arylthio group(e.g., phenylthio, naphthylthio), a C₇₋₁₆ aralkylthio group (e.g.,benzylthio, phenethylthio), a C₁₋₆ alkyl-carbonylthio group (e.g.,acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), aC₆₋₁₄ aryl-carbonylthio group (e.g., benzoylthio), a 5- to 14-memberedaromatic heterocyclylthio group (e.g., pyridylthio) and a halogenatedthio group (e.g., pentafluorothio).

In the present specification, examples of the “optionally substitutedsilyl group” include a silyl group optionally having “1 to 3substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group and a C₇₋₁₆ aralkyl group,each of which optionally has 1 to 3 substituents selected fromSubstituent group A”.

Preferable examples of the optionally substituted silyl group include atri-C₁₋₆ alkylsilyl group (e.g., trimethylsilyl,tert-butyl(dimethyl)silyl).

In the present specification, examples of the “C₁₋₆ alkylene group”include —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—,—CH(CH₃)—, —C(CH₃)₂—, —CH(C₂H₅)—, —CH(C₃H₇)—, —CH(CH(CH₃)₂)—,—(CH(CH₃))₂—, —CH₂—CH(CH₃)—, —CH(CH₃)—CH₂—, —CH₂—CH₂—C(CH₃)₂—,—C(CH₃)₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—C(CH₃)₂— and —C(CH₃)₂—CH₂—CH₂—CH₂—.

In the present specification, examples of the “C₂₋₆ alkenylene group”include —CH═CH—, —CH₂—CH═CH—, —CH═CH—CH₂—, —C(CH₃)₂—CH═CH—,—CH═CH—C(CH₃)₂—, —CH₂—CH═CH—CH₂—, —CH₂—CH₂—CH═CH—, —CH═CH—CH₂—CH₂—,—CH═CH—CH═CH—, —CH═CH—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH═CH—.

In the present specification, examples of the “C₂₋₆ alkynylene group”include —C≡C—, —CH₂—C≡C—, —C≡C—CH₂—, —C(CH₃)₂—C≡C—, —C≡C—C(CH₃)₂—,—CH₂—C≡C—CH₂—, —CH₂—CH₂—C≡C—, —C≡C—CH₂—CH₂—, —C≡C—C≡C—,—C≡C—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—C≡C—.

As shown in the formula:

in the present specification, when the non-aromatic Ring Q, which isfused with the aromatic Ring Q′, is present, then the non-aromatic RingQ is expressed as a ring wherein the bond C¹C² is a double bond.

For example, when the above-mentioned fused Ring QQ′ is an indane ring,then the non-aromatic Ring Q is expressed as a cyclopentene ring, andthe aromatic Ring Q′ is expressed as a benzene ring.

For example, when the above-mentioned fused Ring QQ′ is a2,3-dihydrobenzofuran ring, then the non-aromatic Ring Q is expressed asa dihydrofuran ring (e.g., 2,3-dihydrofuran), and the aromatic Ring Q′is expressed as a benzene ring.

For example, when the above-mentioned fused Ring QQ′ is a1,3-benzodioxole ring, then the non-aromatic Ring Q is expressed as adioxole ring (e.g., 1,3-dioxole), and the aromatic Ring Q′ is expressedas a benzene ring.

For example, when the above-mentioned fused Ring QQ′ is a2,3-dihydro-1,4-benzodioxin ring, then the non-aromatic Ring Q isexpressed as a dihydrodioxin ring (e.g., 2,3-dihydro-1,4-dioxin), andthe aromatic Ring Q′ is expressed as a benzene ring.

The definition of each symbol in the formulas (I) and (Ia) is explainedin detail in the following.

Ring A is an optionally further substituted 6-membered aromatic ring.

Examples of the “6-membered aromatic ring” of the “optionally furthersubstituted 6-membered aromatic ring” for Ring A include a benzene ring,a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ringand a triazine ring.

The “6-membered aromatic ring” is optionally further substituted, forexample, by substituent(s) selected from the above-mentioned SubstituentGroup A. The number of the substituents is, for example, 1 to 3. Whenthe number of the substituents is 2 or more, the respective substituentsmay be the same or different.

Ring A is preferably a 6-membered aromatic ring (e.g., a benzene ring, apyridine ring) optionally further substituted by 1 to 3 (preferably 1 or2) substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (3) a cyano group.

Ring A is more preferably a benzene ring optionally further substitutedby 1 to 3 (preferably 1 or 2) substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (2) a cyano group.

Ring A is still more preferably a benzene ring optionally furthersubstituted by 1 to 3 (preferably 1 or 2) halogen atoms (e.g., afluorine atom).

In another embodiment, Ring A is more preferably a benzene ringoptionally further substituted by halogen atom(s) (e.g., a fluorineatom, a chlorine atom) or cyano group(s).

Ring A is still more preferably a benzene ring optionally furthersubstituted by halogen atom(s) (e.g., a fluorine atom).

R¹ is

(1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))wherein Q is a carbon atom, a silicon atom or a germanium atom, andR^(1a), R^(1b) and R^(1c) are each independently a substituent, orR^(1a) and R^(1b) in combination optionally form, together with theadjacent Q, an optionally further substituted ring, and R^(1c) isoptionally bonded to one substituent for Ring A to form an optionallyfurther substituted ring,(2) a neo-pentyl group, or(3) a trimethylsilylmethyl group.

Examples of the “optionally substituted ring” formed by R^(1a) andR^(1b) in combination together with the adjacent Q include a C₃₋₁₀cycloalkane ring, a C₃₋₁₀ cycloalkene ring and a non-aromaticheterocycle (including a 3- to 14-membered non-aromatic heterocycle),each of which is optionally further substituted by substituent(s)selected from the above-mentioned Substituent Group A. The number of thesubstituents in the “optionally substituted ring” is, for example, 1 to3. When the number of the substituents is 2 or more, the respectivesubstituents may be the same or different.

Examples of the “C₃₋₁₀ cycloalkane ring” exemplified as the “optionallysubstituted ring” formed by R^(1a) and R^(1b) in combination togetherwith the adjacent Q include a ring corresponding to the above-mentioned“C₃₋₁₀ cycloalkyl group”.

Examples of the “C₃₋₁₀ cycloalkene ring” exemplified as the “optionallysubstituted ring” formed by R^(1a) and R^(1b) in combination togetherwith the adjacent Q include a ring corresponding to the above-mentioned“C₃₋₁₀ cycloalkenyl group”.

Examples of the “non-aromatic heterocycle” exemplified as the“optionally substituted ring” formed by R^(1a) and R^(1b) in combinationtogether with the adjacent Q include a ring corresponding to theabove-mentioned “non-aromatic heterocyclic group”.

Examples of the “optionally further substituted ring” formed by R^(1c)and one substituent for Ring A in combination include a C₃₋₁₀cycloalkene ring and a non-aromatic heterocycle (including a 3- to14-membered non-aromatic heterocycle), each of which is optionallyfurther substituted by substituent(s) selected from the above-mentionedSubstituent Group A. The number of the substituents in the “optionallysubstituted ring” is, for example, 1 to 3. When the number of thesubstituents is 2 or more, the respective substituents may be the sameor different.

Examples of the “C₃₋₁₀ cycloalkene ring” exemplified as the “optionallyfurther substituted ring” formed by R^(1c) and one substituent for RingA in combination include a ring corresponding to the above-mentioned“C₃₋₁₀ cycloalkenyl group”.

Examples of the “non-aromatic heterocycle” exemplified as the“optionally further substituted ring” formed by R^(1c) and onesubstituent for Ring A in combination include a ring corresponding tothe above-mentioned “non-aromatic heterocyclic group”.

When R^(1c) is bonded to one substituent for Ring A to form an“optionally further substituted ring”, in the formula (I) or formula(Ia), the partial structure represented by the formula:

wherein * is a binding site, and the other symbols are as defined above,is preferably the partial structure represented by the formula:

wherein Ring E is a “optionally further substituted ring” formed byR^(1c) and one substituent for Ring A, and the other symbols are asdefined above,more preferably the partial structure represented by the formula:

wherein each symbol is as defined above, still more preferably thepartial structure represented by the formula:

wherein X³ is a methylene group or an oxygen atom, and the other symbolsare as defined above,(which is the partial structure wherein R^(1c) is bonded to onesubstituent for Ring A to form a dihydrofuran ring (one example) or acyclopentene ring),particularly preferably the partial structure represented by theformula:

(which is the partial structure wherein R^(1c) is bonded to onesubstituent for Ring A to form a cyclopentene ring).

Q is preferably a carbon atom or a silicon atom.

R^(1a) and R^(1b) is preferably each independently a C₁₋₆ alkyl group(e.g., methyl).

R^(1c) is preferably

(a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 3 C₁₋₆ alkoxy groups (e.g., methoxy, ethoxy) optionally substitutedby 1 to 3 substituents selected from

(i) a halogen atom (e.g., a fluorine atom),

(ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), and

(iii) a C₁₋₆ alkoxy group (e.g., methoxy),

(b) a C₁₋₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl),(c) a carbamoyl group optionally mono- or di-substituted bysubstituent(s) selected from

(i) a C₁₋₆ alkyl group (e.g., ethyl), and

(ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),

(d) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,oxadiazolyl (1,3,4-oxadiazolyl)) optionally substituted by 1 to 3 C₁₋₆alkyl groups (e.g., methyl), or(e) a 3- to 8-membered monocyclic non-aromatic heterocyclylcarbonylgroup (e.g., pyrrolidinylcarbonyl).

R^(1c) is more preferably

(a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 3 C₁₋₆ alkoxy groups (e.g., methoxy, ethoxy) optionally substitutedby 1 to 3 substituents selected from

(i) a halogen atom (e.g., a fluorine atom),

(ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), and

(iii) a C₁₋₆ alkoxy group (e.g., methoxy),

(b) a C₁₋₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl), or(c) a 3- to 8-membered monocyclic non-aromatic heterocyclylcarbonylgroup (e.g., pyrrolidinylcarbonyl).

R^(1c) is particularly preferably a C₁₋₆ alkyl group (e.g., methyl).

Alternatively, R^(1c) is bonded to one substituent for Ring A to formpreferably

(a) a C₃₋₁₀ cycloalkene ring (e.g., cyclopentene), or(b) a 3- to 14-membered non-aromatic heterocycle (e.g., dihydrofuran),more preferably a C₃₋₁₀ cycloalkene ring (e.g., cyclopentene).

R¹ is preferably

(1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))

-   -   wherein    -   Q is a carbon atom or a silicon atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy, ethoxy)        optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine        atom),    -   (b) a C₁₋₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl),    -   (c) a carbamoyl group optionally mono- or di-substituted by        substituent(s) selected from        -   (i) a C₁₋₆ alkyl group (e.g., ethyl), and        -   (ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),    -   (d) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., oxadiazolyl (1,3,4-oxadiazolyl)) optionally substituted        by 1 to 3 C₁₋₆ alkyl groups (e.g., methyl), or    -   (e) a 3- to 8-membered monocyclic non-aromatic        heterocyclylcarbonyl group (e.g., pyrrolidinylcarbonyl), or        R^(1c) is bonded to one substituent for Ring A to form    -   (a) a C₃₋₁₀ cycloalkene ring (e.g., cyclopentene), or    -   (b) a 3- to 14-membered non-aromatic heterocycle (e.g.,        dihydrofuran), or        (2) a neo-pentyl group.

R¹ is more preferably a group represented by the formula:

-Q(R^(1a))(R^(1b))(R^(1c))

-   -   wherein    -   Q is a carbon atom or a silicon atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently    -   (a) a C₁₋₆ alkyl group (e.g., methyl), or    -   (b) a C₁₋₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl), or        R^(1c) is bonded to one substituent for Ring A to form a C₃₋₁₀        cycloalkene ring (e.g., cyclopentene).

In another embodiment, R¹ is preferably

(1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))

-   -   wherein    -   Q is a carbon atom or a silicon atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy, ethoxy)        optionally substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (b) a C₁₋₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl),    -   (c) a carbamoyl group optionally mono- or di-substituted by        substituent(s) selected from        -   (i) a C₁₋₆ alkyl group (e.g., ethyl), and        -   (ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),    -   (d) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., oxadiazolyl (1,3,4-oxadiazolyl)) optionally substituted        by 1 to 3 C₁₋₆ alkyl groups (e.g., methyl), or    -   (e) a 3- to 8-membered monocyclic non-aromatic        heterocyclylcarbonyl group (e.g., pyrrolidinylcarbonyl), or        R^(1a) is bonded to one substituent for Ring A to form    -   (a) a C₃₋₁₀ cycloalkene ring (e.g., cyclopentene), or    -   (b) a 3- to 14-membered non-aromatic heterocycle (e.g.,        dihydrofuran), or        (2) a neo-pentyl group.

R¹ is more preferably a group represented by the formula:

-Q(R^(1a))(R^(1b))(R^(1c))

-   -   wherein    -   Q is a carbon atom or a silicon atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy, ethoxy)        optionally substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (b) a C₁₋₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl), or    -   (c) a 3- to 8-membered monocyclic non-aromatic        heterocyclylcarbonyl group (e.g., pyrrolidinylcarbonyl), or        R^(1c) is bonded to one substituent for Ring A to form a C₃₋₁₀        cycloalkene ring (e.g., cyclopentene).

R¹ is particularly preferably a group represented by the formula:-Q(R^(1a))(R^(1b))(R^(1c))

-   -   wherein    -   Q is a carbon atom or a silicon atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently a C₁₋₆ alkyl        group (e.g., methyl), or    -   R^(1c) is bonded to one substituent for Ring A to form a C₃₋₁₀        cycloalkene ring (e.g., cyclopentene).

In another embodiment, R¹ is preferably

(1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))

-   -   wherein    -   Q is a carbon atom or a silicon atom,    -   R^(1a) and R^(1b) are each independently a C₁₋₆ alkyl group        (e.g., methyl), and    -   R^(1c) is    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy, ethoxy)        optionally substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (b) a C₁₋₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl),    -   (c) a carbamoyl group optionally mono- or di-substituted by        substituent(s) selected from        -   (i) a C₁₋₆ alkyl group (e.g., ethyl), and        -   (ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),    -   (d) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., oxadiazolyl (1,3,4-oxadiazolyl)) optionally substituted        by 1 to 3 C₁₋₆ alkyl groups (e.g., methyl), or    -   (e) a 3- to 8-membered monocyclic non-aromatic        heterocyclylcarbonyl group (e.g., pyrrolidinylcarbonyl), or        R^(1c) is bonded to one substituent for Ring A to form    -   (a) a C₃₋₁₀ cycloalkene ring (e.g., cyclopentene), or    -   (b) a 3- to 14-membered non-aromatic heterocycle (e.g.,        dihydrofuran), or        (2) a neo-pentyl group.

R¹ is more preferably a group represented by the formula:

-Q(R^(1a))(R^(1b))(R^(1c))

-   -   wherein    -   Q is a carbon atom or a silicon atom,    -   R^(1a) and R^(1b) are each independently a C₁₋₆ alkyl group        (e.g., methyl), and    -   R^(1c) is    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy, ethoxy)        optionally substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (b) a C₁₋₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl), or    -   (c) a 3- to 8-membered monocyclic non-aromatic        heterocyclylcarbonyl group (e.g., pyrrolidinylcarbonyl), or        R^(1c) is bonded to one substituent for Ring A to form a C₃₋₁₀        cycloalkene ring (e.g., cyclopentene).

In another embodiment, R¹ is preferably a trimethylsilyl group, anethyldimethylsilyl group or an optionally substituted tert-butyl group,or a group represented by the formula: —C(R^(1a))(R^(1b))(R^(1c))wherein R^(1a) and R^(1b) are each independently a substituent, orR^(1a) and R^(1b) in combination optionally form, together with theadjacent carbon atom, an optionally further substituted ring, and R^(1c)is bonded to one substituent for Ring A to form an optionally furthersubstituted ring.

Examples of the “optionally substituted tert-butyl group” for R¹ includea tert-butyl group optionally substituted by substituent(s) selectedfrom the above-mentioned Substituent Group A. The number of thesubstituents in the “optionally substituted tert-butyl group” is, forexample, 1 to 5, preferably 1 to 3. When the number of the substituentsis 2 or more, the respective substituents may be the same or different.

R¹ is more preferably

(1) (a) a trimethylsilyl group,

-   -   (b) an ethyldimethylsilyl group, or    -   (c) a tert-butyl group optionally substituted by 1 to 3 C₁₋₆        alkoxy groups (e.g., methoxy, ethoxy) optionally substituted by        1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy), or            (2) a group represented by the formula:            —C(R^(1a))(R^(1b))(R^(1c))    -   wherein    -   R^(1a) and R^(1b) are each independently a C₁₋₆ alkyl group        (e.g., methyl), and    -   R^(1c) is bonded to one substituent for Ring A to form a C₃₋₁₀        cycloalkene ring (e.g., cyclopentene).

In one embodiment, in formula (I) or formula (Ia), the partial structurerepresented by the formula:

wherein each symbol is as defined above,is preferably the partial structure selected from the formula:

wherein each symbol is as defined above,more preferably the partial structure selected from the formula:

wherein each symbol is as defined above,still more preferably the partial structure selected from the formula:

wherein each symbol is as defined above,particularly preferably the partial structure selected from the formula:

wherein each symbol is as defined above.

R¹¹ is —CR¹²R^(12′)—R^(12″), —C(═O)—R⁴ or —SO₂—R¹³.

R¹¹ is preferably —C(═O)—R⁴.

R¹², R^(12′) and R^(12″) are each independently a hydrogen atom, ahalogen atom, a cyano group, a nitro group, an optionally substitutedC₁₋₆ alkyl group, an optionally substituted C₂₋₆ alkenyl group, anoptionally substituted C₂₋₆ alkynyl group, an optionally substitutedheterocyclic group or an optionally substituted thiocarbamoyl group.

The “optionally substituted C₁₋₆ alkyl group”, “optionally substitutedC₂₋₆ alkenyl group”, “optionally substituted C₂₋₆ alkynyl group”,“optionally substituted heterocyclic group” and the “optionallysubstituted thiocarbamoyl group” for R¹², R^(12′) or R^(12″) are eachoptionally substituted by 1 to 5 (preferably 1 to 3) substituentsselected from Substituent Group A. When the number of the substituentsis 2 or more, the respective substituents may be the same or different.

Preferably, R¹² is a hydrogen atom, a halogen atom, a cyano group, anitro group, an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted C₂₋₆ alkenyl group, an optionally substituted C₂₋₆ alkynylgroup, an optionally substituted heterocyclic group or an optionallysubstituted thiocarbamoyl group, and R^(12″) and R^(12″) are hydrogenatoms.

More preferably, R¹² is an optionally substituted C₁₋₆ alkyl group, andR^(12′) and R^(12″) are hydrogen atoms.

Still more preferably, R¹² is a C₁₋₆ alkyl group (e.g., ethyl)optionally substituted by 1 to 3 C₁₋₆ alkoxy-carbonyl groups (e.g.,methoxycarbonyl), and R^(12′) and R^(12″) are hydrogen atoms.

R⁴ is a halogen atom, a cyano group, a nitro group, an optionallysubstituted C₁₋₆ alkyl group, an optionally substituted C₂₋₆ alkenylgroup, an optionally substituted C₂₋₆ alkynyl group, an optionallysubstituted heterocyclic group, an acyl group, an optionally substitutedamino group, an optionally substituted carbamoyl group, an optionallysubstituted thiocarbamoyl group, an optionally substituted sulfamoylgroup, an optionally substituted hydroxy group, an optionallysubstituted sulfanyl(SH) group or an optionally substituted silyl group,

wherein the “C₁₋₆ alkyl group”, “C₂₋₆ alkenyl group” and “C₂₋₆ alkynylgroup” of the “optionally substituted C₁₋₆ alkyl group”, “optionallysubstituted C₂₋₆ alkenyl group” and “optionally substituted C₂₋₆ alkynylgroup” for R⁴ are each optionally substituted by 1 to 5 (preferably 1 to3) substituents selected from

-   -   (1) a halogen atom,    -   (2) a nitro group,    -   (3) a cyano group,    -   (4) an oxo group,    -   (5) a hydroxy group,    -   (6) an optionally halogenated C₁₋₆ alkoxy group,    -   (7) a C₆₋₁₄ aryloxy group (e.g., phenoxy, naphthoxy),    -   (8) a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy),    -   (9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,        pyridyloxy),    -   (10) a 3- to 14-membered non-aromatic heterocyclyloxy group        (e.g., morpholinyloxy, piperidinyloxy),    -   (11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy,        propanoyloxy),    -   (12) a C₆₋₁₄ aryl-carbonyloxy group (e.g., benzoyloxy,        1-naphthoyloxy, 2-naphthoyloxy),    -   (13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,        ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),    -   (14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,        methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,        diethylcarbamoyloxy),    -   (15) a C₆₋₁₄ aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy,        naphthylcarbamoyloxy),    -   (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group        (e.g., nicotinoyloxy),    -   (17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy        group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),    -   (18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group        (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy),    -   (19) a C₆₋₁₄ arylsulfonyloxy group (e.g., phenylsulfonyloxy,        toluenesulfonyloxy) optionally substituted by C₁₋₆ alkyl        group(s),    -   (20) an optionally halogenated C₁₋₆ alkylthio group,    -   (21) a 5- to 14-membered aromatic heterocyclic group,    -   (22) a 3- to 14-membered non-aromatic heterocyclic group,    -   (23) a formyl group,    -   (24) a carboxy group,    -   (25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,    -   (26) a C₆₋₁₄ aryl-carbonyl group,    -   (27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,    -   (28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl        group,    -   (29) a C₁₋₆ alkoxy-carbonyl group,    -   (30) a C₆₋₁₄ aryloxy-carbonyl group (e.g., phenyloxycarbonyl,        l-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),    -   (31) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,        phenethyloxycarbonyl),    -   (32) a carbamoyl group,    -   (33) a thiocarbamoyl group,    -   (34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,    -   (35) a C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl),    -   (36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group        (e.g., pyridylcarbamoyl, thienylcarbamoyl),    -   (37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl        group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl),    -   (38) an optionally halogenated C₁₋₆ alkylsulfonyl group,    -   (39) a C₆₋₁₄ arylsulfonyl group,    -   (40) a 5- to 14-membered aromatic heterocyclylsulfonyl group        (e.g., pyridylsulfonyl, thienylsulfonyl),    -   (41) an optionally halogenated C₁₋₆ alkylsulfinyl group,    -   (42) a C₆₋₁₄ arylsulfinyl group (e.g., phenylsulfinyl,        1-naphthylsulfinyl, 2-naphthylsulfinyl),    -   (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group        (e.g., pyridylsulfinyl, thienylsulfinyl),    -   (44) an amino group,    -   (45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino,        ethylamino, propylamino, isopropylamino, butylamino,        dimethylamino, diethylamino, dipropylamino, dibutylamino,        N-ethyl-N-methylamino),    -   (46) a mono- or di-C₆₋₁₄ arylamino group (e.g., phenylamino),    -   (47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,        pyridylamino),    -   (48) a C₇₋₁₆ aralkylamino group (e.g., benzylamino),    -   (49) a formylamino group,    -   (50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,        propanoylamino, butanoylamino),    -   (51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group (e.g.,        N-acetyl-N-methylamino),    -   (52) a C₆₋₁₄ aryl-carbonylamino group (e.g.,        phenylcarbonylamino, naphthylcarbonylamino),    -   (53) a C₁₋₆ alkoxy-carbonylamino group (e.g.,        methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,        butoxycarbonylamino, tert-butoxycarbonylamino),    -   (54) a C₇₋₁₆ aralkyloxy-carbonylamino group (e.g.,        benzyloxycarbonylamino),    -   (55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,        ethylsulfonylamino),    -   (56) a C₆₋₁₄ arylsulfonylamino group (e.g., phenylsulfonylamino,        toluenesulfonylamino) optionally substituted by C₁₋₆ alkyl        group(s),    -   (57) an optionally halogenated C₁₋₆ alkyl group,    -   (58) a C₂₋₆ alkenyl group, and    -   (59) a C₂₋₆ alkynyl group.        When the number of the substituents is 2 or more, the respective        substituents may be the same or different.

In another embodiment, R⁴ is an optionally substituted C₁₋₆ alkyl group,an optionally substituted C₂₋₆ alkenyl group, an optionally substitutedC₂₋₆alkynyl group, an optionally substituted heterocyclic group, an acylgroup, an optionally substituted amino group, an optionally substitutedcarbamoyl group, an optionally substituted thiocarbamoyl group, anoptionally substituted sulfamoyl group, an optionally substitutedhydroxy group, an optionally substituted sulfanyl(SH) group or anoptionally substituted silyl group,

wherein the “C₁₋₆ alkyl group”, “C₂₋₆ alkenyl group” and “C₂₋₆ alkynylgroup” of the “optionally substituted C₁₋₆ alkyl group”, “optionallysubstituted C₂₋₆ alkenyl group” and “optionally substituted C₂₋₆alkynylgroup” for R⁴ are each optionally substituted by 1 to 5 (preferably 1 to3) substituents selected from

-   -   (1) a halogen atom,    -   (2) a nitro group,    -   (3) a cyano group,    -   (4) an oxo group,    -   (5) a hydroxy group,    -   (6) a C₁₋₆ alkoxy group optionally substituted by substituent(s)        selected from a halogen atom and a carboxy group,    -   (7) a C₆₋₁₄ aryloxy group (e.g., phenoxy, naphthoxy),    -   (8) a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy),    -   (9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,        pyridyloxy),    -   (10) a 3- to 14-membered non-aromatic heterocyclyloxy group        (e.g., morpholinyloxy, piperidinyloxy),    -   (11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy,        propanoyloxy),    -   (12) a C₆₋₁₄ aryl-carbonyloxy group (e.g., benzoyloxy,        1-naphthoyloxy, 2-naphthoyloxy),    -   (13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,        ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),    -   (14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,        methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,        diethylcarbamoyloxy),    -   (15) a C₆₋₁₄ aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy,        naphthylcarbamoyloxy),    -   (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group        (e.g., nicotinoyloxy),    -   (17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy        group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),    -   (18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group        (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy),    -   (19) a C₆₋₁₄ arylsulfonyloxy group (e.g., phenylsulfonyloxy,        toluenesulfonyloxy) optionally substituted by C₁₋₆ alkyl        group(s),    -   (20) an optionally halogenated C₁₋₆ alkylthio group,    -   (21) a 5- to 14-membered aromatic heterocyclic group optionally        substituted by substituent(s) selected from a hydroxy group, a        C₁₋₆ alkyl group, a C₁₋₆ alkoxy group and a carboxy group,    -   (22) a 3- to 14-membered non-aromatic heterocyclic group        optionally substituted by substituent(s) selected from an oxo        group and a C₁₋₆ alkyl group,    -   (23) a formyl group,    -   (24) a carboxy group,    -   (25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,    -   (26) a C₆₋₁₄ aryl-carbonyl group,    -   (27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,    -   (28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl        group,    -   (29) a C₁₋₆ alkoxy-carbonyl group,    -   (30) a C₆₋₁₄ aryloxy-carbonyl group (e.g., phenyloxycarbonyl,        1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),    -   (31) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,        phenethyloxycarbonyl),    -   (32) a carbamoyl group,    -   (33) a thiocarbamoyl group,    -   (34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,    -   (35) a C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl),    -   (36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group        (e.g., pyridylcarbamoyl, thienylcarbamoyl),    -   (37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl        group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl),    -   (38) an optionally halogenated C₁₋₆ alkylsulfonyl group,    -   (39) a C₆₋₁₄ arylsulfonyl group,    -   (40) a 5- to 14-membered aromatic heterocyclylsulfonyl group        (e.g., pyridylsulfonyl, thienylsulfonyl),    -   (41) an optionally halogenated C₁₋₆ alkylsulfinyl group,    -   (42) a C₆₋₁₄ arylsulfinyl group (e.g., phenylsulfinyl,        1-naphthylsulfinyl, 2-naphthylsulfinyl),    -   (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group        (e.g., pyridylsulfinyl, thienylsulfinyl),    -   (44) an amino group,    -   (45) a mono- or di-C₁₋₆ alkylamino group (the C₁₋₆ alkyl is        optionally substituted by carboxy group(s)) (e.g., methylamino,        ethylamino, propylamino, isopropylamino, butylamino,        dimethylamino, diethylamino, dipropylamino, dibutylamino,        N-ethyl-N-methylamino, N-(carboxymethyl)-N-methylamino),    -   (46) a mono- or di-C₆₋₁₄ arylamino group (e.g., phenylamino),    -   (47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,        pyridylamino),    -   (48) a C₇₋₁₆ aralkylamino group (e.g., benzylamino),    -   (49) a formylamino group,    -   (50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,        propanoylamino, butanoylamino),    -   (51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group (e.g.,        N-acetyl-N-methylamino),    -   (52) a C₆₋₁₄ aryl-carbonylamino group (e.g.,        phenylcarbonylamino, naphthylcarbonylamino),    -   (53) a C₁₋₆ alkoxy-carbonylamino group (e.g.,        methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,        butoxycarbonylamino, tert-butoxycarbonylamino),    -   (54) a C₇₋₁₆ aralkyloxy-carbonylamino group (e.g.,        benzyloxycarbonylamino),    -   (55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,        ethylsulfonylamino),    -   (56) a C₆₋₁₄ arylsulfonylamino group (e.g., phenylsulfonylamino,        toluenesulfonylamino) optionally substituted by C₁₋₆ alkyl        group(s),    -   (57) an optionally halogenated C₁₋₆ alkyl group,    -   (58) a C₂₋₆ alkenyl group, and    -   (59) a C₂₋₆ alkynyl group.        When the number of the substituents is 2 or more, the respective        substituents may be the same or different.

In another embodiment, R⁴ is a halogen atom, a cyano group, a nitrogroup, an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted C₂₋₆ alkenyl group, an optionally substituted C₂₋₆ alkynylgroup, an optionally substituted heterocyclic group, an acyl group, anoptionally substituted amino group, an optionally substituted carbamoylgroup, an optionally substituted thiocarbamoyl group, an optionallysubstituted sulfamoyl group, an optionally substituted hydroxy group, anoptionally substituted sulfanyl(SH) group or an optionally substitutedsilyl group,

wherein the substituents which the “optionally substituted C₁₋₆ alkylgroup”, “optionally substituted C₂₋₆ alkenyl group”, “optionallysubstituted C₂₋₆ alkynyl group” and “optionally substituted heterocyclicgroup” for R⁴ optionally have are each selected from

-   -   (1) a halogen atom,    -   (2) a nitro group,    -   (3) a cyano group,    -   (4) an oxo group,    -   (5) a hydroxy group,    -   (6) an optionally halogenated C₁₋₆ alkoxy group,    -   (9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,        pyridyloxy),    -   (10) a 3- to 14-membered non-aromatic heterocyclyloxy group        (e.g., morpholinyloxy, piperidinyloxy),    -   (11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy,        propanoyloxy),    -   (13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,        ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),    -   (14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,        methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,        diethylcarbamoyloxy),    -   (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group        (e.g., nicotinoyloxy),    -   (17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy        group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),    -   (18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group        (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy),    -   (20) an optionally halogenated C₁₋₆ alkylthio group,    -   (21) a 5- to 14-membered aromatic heterocyclic group,    -   (22) a 3- to 14-membered non-aromatic heterocyclic group,    -   (23) a formyl group,    -   (24) a carboxy group,    -   (25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,    -   (27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,    -   (28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl        group,    -   (29) a C₁₋₆ alkoxy-carbonyl group,    -   (32) a carbamoyl group,    -   (33) a thiocarbamoyl group,    -   (34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,    -   (36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group        (e.g., pyridylcarbamoyl, thienylcarbamoyl),    -   (37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl        group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl),    -   (38) an optionally halogenated C₁₋₆ alkylsulfonyl group,    -   (40) a 5- to 14-membered aromatic heterocyclylsulfonyl group        (e.g., pyridylsulfonyl, thienylsulfonyl),    -   (41) an optionally halogenated C₁₋₆ alkylsulfinyl group,    -   (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group        (e.g., pyridylsulfinyl, thienylsulfinyl),    -   (44) an amino group,    -   (45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino,        ethylamino, propylamino, isopropylamino, butylamino,        dimethylamino, diethylamino, dipropylamino, dibutylamino,        N-ethyl-N-methylamino),    -   (47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,        pyridylamino),    -   (49) a formylamino group,    -   (50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,        propanoylamino, butanoylamino),    -   (51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group (e.g.,        N-acetyl-N-methylamino),    -   (53) a C₁₋₆ alkoxy-carbonylamino group (e.g.,        methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,        butoxycarbonylamino, tert-butoxycarbonylamino),    -   (55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,        ethylsulfonylamino),    -   (57) an optionally halogenated C—, alkyl group,    -   (58) a C₂₋₆ alkenyl group, and    -   (59) a C₂₋₆ alkynyl group.        The number of the substituents is 1 to 5 (preferably 1 to 3).        When the number of the substituents is 2 or more, the respective        substituents may be the same or different.

In another embodiment, R⁴ is an optionally substituted C₁₋₆ alkyl group,an optionally substituted C₂₋₆ alkenyl group, an optionally substitutedC₂₋₆ alkynyl group, an optionally substituted heterocyclic group, anacyl group, an optionally substituted amino group, an optionallysubstituted carbamoyl group, an optionally substituted thiocarbamoylgroup, an optionally substituted sulfamoyl group, an optionallysubstituted hydroxy group, an optionally substituted sulfanyl(SH) groupor an optionally substituted silyl group,

Wherein the substituents for the “C₁₋₆ alkyl group”, “C₂₋₆ alkenylgroup” and “C₂₋₆ alkynyl group” of the “optionally substituted C₁₋₆alkyl group”, “optionally substituted C₂₋₆ alkenyl group” and“optionally substituted C₂₋₆ alkynyl group” for R⁴ are each selectedfrom

-   -   (1) a halogen atom,    -   (2) a nitro group,    -   (3) a cyano group,    -   (4) an oxo group,    -   (5) a hydroxy group,    -   (6) a C₁₋₆ alkoxy group optionally substituted by substituent(s)        selected from a halogen atom and a carboxy group,    -   (9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,        pyridyloxy),    -   (10) a 3- to 14-membered non-aromatic heterocyclyloxy group        (e.g., morpholinyloxy, piperidinyloxy),    -   (11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy,        propanoyloxy),    -   (13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,        ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),    -   (14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,        methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,        diethylcarbamoyloxy),    -   (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group        (e.g., nicotinoyloxy),    -   (17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy        group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),    -   (18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group        (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy),    -   (20) an optionally halogenated C₁₋₆ alkylthio group,    -   (21) a 5- to 14-membered aromatic heterocyclic group optionally        substituted by substituent(s) selected from a hydroxy group, a        C₁₋₆ alkyl group, a C₁₋₆ alkoxy group and a carboxy group,    -   (22) a 3- to 14-membered non-aromatic heterocyclic group        optionally substituted by substituent(s) selected from an oxo        group and a C₁₋₆ alkyl group,    -   (23) a formyl group,    -   (24) a carboxy group,    -   (25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,    -   (27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,    -   (28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl        group,    -   (29) a C₁₋₆ alkoxy-carbonyl group,    -   (32) a carbamoyl group,    -   (33) a thiocarbamoyl group,    -   (34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,    -   (36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group        (e.g., pyridylcarbamoyl, thienylcarbamoyl),    -   (37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl        group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl),    -   (38) an optionally halogenated C₁₋₆ alkylsulfonyl group,    -   (40) a 5- to 14-membered aromatic heterocyclylsulfonyl group        (e.g., pyridylsulfonyl, thienylsulfonyl),    -   (41) an optionally halogenated C₁₋₆ alkylsulfinyl group,    -   (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group        (e.g., pyridylsulfinyl, thienylsulfinyl),    -   (44) an amino group,    -   (45) a mono- or di-C₁₋₆ alkylamino group (the C₁₋₆ alkyl is        optionally substituted by carboxy group(s)) (e.g., methylamino,        ethylamino, propylamino, isopropylamino, butylamino,        dimethylamino, diethylamino, dipropylamino, dibutylamino,        N-ethyl-N-methylamino, N-(carboxymethyl)-N-methylamino),    -   (47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,        pyridylamino),    -   (49) a formylamino group,    -   (50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,        propanoylamino, butanoylamino),    -   (51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group (e.g.,        N-acetyl-N-methylamino),    -   (53) a C₁₋₆ alkoxy-carbonylamino group (e.g.,        methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,        butoxycarbonylamino, tert-butoxycarbonylamino),    -   (55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,        ethylsulfonylamino),    -   (57) an optionally halogenated C₁₋₆ alkyl group,    -   (58) a C₂₋₆ alkenyl group, and    -   (59) a C₂₋₆ alkynyl group.        The number of the substituents is 1 to 5 (preferably 1 to 3).        When the number of the substituents is 2 or more, the respective        substituents may be the same or different.

The substituent which the “optionally substituted heterocyclic group”for R⁴ optionally has is selected from

-   -   (1) a halogen atom,    -   (2) a nitro group,    -   (3) a cyano group,    -   (4) an oxo group,    -   (5) a hydroxy group,    -   (6) a C₁₋₆ alkoxy group optionally substituted by substituent(s)        selected from a halogen atom and a carboxy group,    -   (9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,        pyridyloxy),    -   (10) a 3- to 14-membered non-aromatic heterocyclyloxy group        (e.g., morpholinyloxy, piperidinyloxy),    -   (11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy,        propanoyloxy),    -   (13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,        ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),    -   (14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,        methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,        diethylcarbamoyloxy),    -   (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group        (e.g., nicotinoyloxy),    -   (17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy        group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),    -   (18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group        (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy),    -   (20) an optionally halogenated C₁₋₆ alkylthio group,    -   (21) a 5- to 14-membered aromatic heterocyclic group,    -   (22) a 3- to 14-membered non-aromatic heterocyclic group,    -   (23) a formyl group,    -   (24) a carboxy group,    -   (25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,    -   (27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,    -   (28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl        group,    -   (29) a C₁₋₆ alkoxy-carbonyl group,    -   (32) a carbamoyl group,    -   (33) a thiocarbamoyl group,    -   (34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,    -   (36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group        (e.g., pyridylcarbamoyl, thienylcarbamoyl),    -   (37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl        group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl),    -   (38) an optionally halogenated C₁₋₆ alkylsulfonyl group,    -   (40) a 5- to 14-membered aromatic heterocyclylsulfonyl group        (e.g., pyridylsulfonyl, thienylsulfonyl),    -   (41) an optionally halogenated C₁₋₆ alkylsulfinyl group,    -   (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group        (e.g., pyridylsulfinyl, thienylsulfinyl),    -   (44) an amino group,    -   (45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino,        ethylamino, propylamino, isopropylamino, butylamino,        dimethylamino, diethylamino, dipropylamino, dibutylamino,        N-ethyl-N-methylamino),    -   (47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,        pyridylamino),    -   (49) a formylamino group,    -   (50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,        propanoylamino, butanoylamino),    -   (51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group (e.g.,        N-acetyl-N-methylamino),    -   (53) a C₁₋₆ alkoxy-carbonylamino group (e.g.,        methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,        butoxycarbonylamino, tert-butoxycarbonylamino),    -   (55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,        ethylsulfonylamino),    -   (57) a C₁₋₆ alkyl group optionally substituted by substituent(s)        selected from a halogen atom, a carboxy group, and a “C₁₋₆        alkoxy-carbonyl optionally substituted by C₆₋₁₄ aryl group(s)”,    -   (58) a C₂₋₆ alkenyl group, and    -   (59) a C₂₋₆ alkynyl group.    -   The number of the substituents is 1 to 5 (preferably 1 to 3).        When the number of the substituents is 2 or more, the respective        substituents may be the same or different.

In one embodiment, examples of the “acyl group” for R⁴ include a formylgroup, a carboxy group, a carbamoyl group, a thiocarbamoyl group, asulfino group, a sulfo group, a sulfamoyl group and a phosphono group,each of which has “1 or 2 substituents selected from a C₁₋₆ alkyl group,a C₂₋₆ alkenyl group, a 5- to 14-membered aromatic heterocyclic groupand a 3- to 14-membered non-aromatic heterocyclic group, each of whichhas 1 to 3 substituents selected from a halogen atom, an optionallyhalogenated C₁₋₆ alkoxy group, a hydroxy group, a nitro group, a cyanogroup, an amino group, a carboxy group and a carbamoyl group”.

In one embodiment, examples of the “optionally substituted amino group”for R⁴ include an amino group optionally having 1 or 2 substituentsselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆alkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonylgroup, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, aC₁₋₆ alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclicgroup, a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group and aC₁₋₆ alkylsulfonyl group, each of which has 1 to 3 substituents selectedfrom

-   -   (1) a halogen atom,    -   (2) a nitro group,    -   (3) a cyano group,    -   (4) an oxo group,    -   (5) a hydroxy group,    -   (6) an optionally halogenated C₁₋₆ alkoxy group,    -   (9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,        pyridyloxy),    -   (10) a 3- to 14-membered non-aromatic heterocyclyloxy group        (e.g., morpholinyloxy, piperidinyloxy),    -   (11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy,        propanoyloxy),    -   (13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,        ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),    -   (14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,        methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,        diethylcarbamoyloxy),    -   (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group        (e.g., nicotinoyloxy),    -   (17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy        group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),    -   (18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group        (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy),    -   (20) an optionally halogenated C₁₋₆ alkylthio group,    -   (21) a 5- to 14-membered aromatic heterocyclic group,    -   (22) a 3- to 14-membered non-aromatic heterocyclic group,    -   (23) a formyl group,    -   (24) a carboxy group,    -   (25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,    -   (27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,    -   (28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl        group,    -   (29) a C₁₋₆ alkoxy-carbonyl group optionally substituted by        C₆₋₁₄ aryl group(s),    -   (32) a carbamoyl group,    -   (33) a thiocarbamoyl group,    -   (34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,    -   (36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group        (e.g., pyridylcarbamoyl, thienylcarbamoyl),    -   (37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl        group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl),    -   (38) an optionally halogenated C₁₋₆ alkylsulfonyl group,    -   (40) a 5- to 14-membered aromatic heterocyclylsulfonyl group        (e.g., pyridylsulfonyl, thienylsulfonyl),    -   (41) an optionally halogenated C₁₋₆ alkylsulfinyl group,    -   (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group        (e.g., pyridylsulfinyl, thienylsulfinyl),    -   (44) an amino group,    -   (45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino,        ethylamino, propylamino, isopropylamino, butylamino,        dimethylamino, diethylamino, dipropylamino, dibutylamino,        N-ethyl-N-methylamino),    -   (47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,        pyridylamino),    -   (49) a formylamino group,    -   (50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,        propanoylamino, butanoylamino),    -   (51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group (e.g.,        N-acetyl-N-methylamino),    -   (53) a C₁₋₆ alkoxy-carbonylamino group (e.g.,        methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,        butoxycarbonylamino, tert-butoxycarbonylamino),    -   (55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,        ethylsulfonylamino),    -   (57) an optionally halogenated C₁₋₆ alkyl group,    -   (58) a C₂₋₆ alkenyl group, and    -   (59) a C₂₋₆ alkynyl group.

When the number of the substituents is 2, the respective substituentsmay be the same or different.

In one embodiment, examples of the “optionally substituted carbamoylgroup” for R⁴ include a carbamoyl group optionally having 1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₁₋₆ alkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group and a mono-or di-C₁₋₆ alkyl-carbamoyl group, each of which has 1 to 3 substituentsselected from

-   -   (1) a halogen atom,    -   (2) a nitro group,    -   (3) a cyano group,    -   (4) an oxo group,    -   (5) a hydroxy group,    -   (6) an optionally halogenated C₁₋₆ alkoxy group,    -   (9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,        pyridyloxy),    -   (10) a 3- to 14-membered non-aromatic heterocyclyloxy group        (e.g., morpholinyloxy, piperidinyloxy),    -   (11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy,        propanoyloxy),    -   (13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,        ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),    -   (14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,        methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,        diethylcarbamoyloxy),    -   (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group        (e.g., nicotinoyloxy),    -   (17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy        group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),    -   (18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group        (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy),    -   (20) an optionally halogenated C₁₋₆ alkylthio group,    -   (21) a 5- to 14-membered aromatic heterocyclic group,    -   (22) a 3- to 14-membered non-aromatic heterocyclic group,    -   (23) a formyl group,    -   (24) a carboxy group,    -   (25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,    -   (27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,    -   (28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl        group,    -   (29) a C₁₋₆ alkoxy-carbonyl group,    -   (32) a carbamoyl group,    -   (33) a thiocarbamoyl group,    -   (34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,    -   (36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group        (e.g., pyridylcarbamoyl, thienylcarbamoyl),    -   (37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl        group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl),    -   (38) an optionally halogenated C₁₋₆ alkylsulfonyl group,    -   (40) a 5- to 14-membered aromatic heterocyclylsulfonyl group        (e.g., pyridylsulfonyl, thienylsulfonyl),    -   (41) an optionally halogenated C₁₋₆ alkylsulfinyl group,    -   (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group        (e.g., pyridylsulfinyl, thienylsulfinyl),    -   (44) an amino group,    -   (45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino,        ethylamino, propylamino, isopropylamino, butylamino,        dimethylamino, diethylamino, dipropylamino, dibutylamino,        N-ethyl-N-methylamino),    -   (47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,        pyridylamino),    -   (49) a formylamino group,    -   (50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,        propanoylamino, butanoylamino),    -   (51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group (e.g.,        N-acetyl-N-methylamino),    -   (53) a C₁₋₆ alkoxy-carbonylamino group (e.g.,        methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,        butoxycarbonylamino, tert-butoxycarbonylamino),    -   (55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,        ethylsulfonylamino),    -   (57) an optionally halogenated C₁₋₆ alkyl group,    -   (58) a C₂₋₆ alkenyl group, and    -   (59) a C₂₋₆ alkynyl group.        When the number of the substituents is 2, the respective        substituents may be the same or different.

In one embodiment, examples of the “optionally substituted thiocarbamoylgroup” for R⁴ include a thiocarbamoyl group optionally having 1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₁₋₆ alkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group and a mono-or di-C₁₋₆ alkyl-carbamoyl group, each of which has 1 to 3 substituentsselected from

-   -   (1) a halogen atom,    -   (2) a nitro group,    -   (3) a cyano group,    -   (4) an oxo group,    -   (5) a hydroxy group,    -   (6) an optionally halogenated C₁₋₆ alkoxy group,    -   (9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,        pyridyloxy),    -   (10) a 3- to 14-membered non-aromatic heterocyclyloxy group        (e.g., morpholinyloxy, piperidinyloxy),    -   (11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy,        propanoyloxy),    -   (13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,        ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),    -   (14) a mono- or di-C₁₋₆, alkyl-carbamoyloxy group (e.g.,        methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,        diethylcarbamoyloxy),    -   (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group        (e.g., nicotinoyloxy),    -   (17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy        group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),    -   (18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group        (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy),    -   (20) an optionally halogenated C₁₋₆ alkylthio group,    -   (21) a 5- to 14-membered aromatic heterocyclic group,    -   (22) a 3- to 14-membered non-aromatic heterocyclic group,    -   (23) a formyl group,    -   (24) a carboxy group,    -   (25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,    -   (27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,    -   (28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl        group,    -   (29) a C₁₋₆ alkoxy-carbonyl group,    -   (32) a carbamoyl group,    -   (33) a thiocarbamoyl group,    -   (34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,    -   (36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group        (e.g., pyridylcarbamoyl, thienylcarbamoyl),    -   (37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl        group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl),    -   (38) an optionally halogenated C₁₋₆ alkylsulfonyl group,    -   (40) a 5- to 14-membered aromatic heterocyclylsulfonyl group        (e.g., pyridylsulfonyl, thienylsulfonyl),    -   (41) an optionally halogenated C₁₋₆ alkylsulfinyl group,    -   (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group        (e.g., pyridylsulfinyl, thienylsulfinyl),    -   (44) an amino group,    -   (45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino,        ethylamino, propylamino, isopropylamino, butylamino,        dimethylamino, diethylamino, dipropylamino, dibutylamino,        N-ethyl-N-methylamino),    -   (47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,        pyridylamino),    -   (49) a formylamino group,    -   (50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,        propanoylamino, butanoylamino),    -   (51) a (C₁₋₆ alkyl)(C₁₋₆ alkyl-carbonyl)amino group (e.g.,        N-acetyl-N-methylamino),    -   (53) a C₁₋₆ alkoxy-carbonylamino group (e.g.,        methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,        butoxycarbonylamino, tert-butoxycarbonylamino),    -   (55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,        ethylsulfonylamino),    -   (57) an optionally halogenated C₁₋₆ alkyl group,    -   (58) a C₂₋₆ alkenyl group, and    -   (59) a C₂₋₆ alkynyl group.        When the number of the substituents is 2, the respective        substituents may be the same or different.

In one embodiment, examples of the “optionally substituted sulfamoylgroup” for R⁴ include a sulfamoyl group optionally having 1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₁₋₆ alkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group and a mono-or di-C₁₋₆ alkyl-carbamoyl group, each of which has 1 to 3 substituentsselected from

-   -   (1) a halogen atom,    -   (2) a nitro group,    -   (3) a cyano group,    -   (4) an oxo group,    -   (5) a hydroxy group,    -   (6) an optionally halogenated C₁₋₆ alkoxy group,    -   (9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,        pyridyloxy),    -   (10) a 3- to 14-membered non-aromatic heterocyclyloxy group        (e.g., morpholinyloxy, piperidinyloxy),    -   (11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy,        propanoyloxy),    -   (13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,        ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),    -   (14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,        methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,        diethylcarbamoyloxy),    -   (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group        (e.g., nicotinoyloxy),    -   (17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy        group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),    -   (18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group        (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy),    -   (20) an optionally halogenated C₁₋₆ alkylthio group,    -   (21) a 5- to 14-membered aromatic heterocyclic group,    -   (22) a 3- to 14-membered non-aromatic heterocyclic group,    -   (23) a formyl group,    -   (24) a carboxy group,    -   (25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,    -   (27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,    -   (28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl        group,    -   (29) a C₁₋₆ alkoxy-carbonyl group,    -   (32) a carbamoyl group,    -   (33) a thiocarbamoyl group,    -   (34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,    -   (36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group        (e.g., pyridylcarbamoyl, thienylcarbamoyl),    -   (37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl        group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl),    -   (38) an optionally halogenated C₁₋₆ alkylsulfonyl group,    -   (40) a 5- to 14-membered aromatic heterocyclylsulfonyl group        (e.g., pyridylsulfonyl, thienylsulfonyl),    -   (41) an optionally halogenated C₁₋₆ alkylsulfinyl group,    -   (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group        (e.g., pyridylsulfinyl, thienylsulfinyl),    -   (44) an amino group,    -   (45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino,        ethylamino, propylamino, isopropylamino, butylamino,        dimethylamino, diethylamino, dipropylamino, dibutylamino,        N-ethyl-N-methylamino),    -   (47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,        pyridylamino),    -   (49) a formylamino group,    -   (50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,        propanoylamino, butanoylamino),    -   (51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group (e.g.,        N-acetyl-N-methylamino),    -   (53) a C₁₋₆ alkoxy-carbonylamino group (e.g.,        methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,        butoxycarbonylamino, tert-butoxycarbonylamino),    -   (55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,        ethylsulfonylamino),    -   (57) an optionally halogenated C₁₋₆ alkyl group,    -   (58) a C₂₋₆ alkenyl group, and    -   (59) a C₂₋₆ alkynyl group.        When the number of the substituents is 2, the respective        substituents may be the same or different.

In one embodiment, examples of the “optionally substituted hydroxygroup” for R⁴ include a hydroxy group optionally having a substituentselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆alkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonylgroup, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, aC₁₋₆ alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclicgroup, a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group and aC₁₋₆ alkylsulfonyl group, each of which has 1 to 3 substituents selectedfrom

-   -   (1) a halogen atom,    -   (2) a nitro group,    -   (3) a cyano group,    -   (4) an oxo group,    -   (5) a hydroxy group,    -   (6) an optionally halogenated C₁₋₆ alkoxy group,    -   (9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,        pyridyloxy),    -   (10) a 3- to 14-membered non-aromatic heterocyclyloxy group        (e.g., morpholinyloxy, piperidinyloxy),    -   (11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy,        propanoyloxy),    -   (13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,        ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),    -   (14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,        methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,        diethylcarbamoyloxy),    -   (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group        (e.g., nicotinoyloxy),    -   (17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy        group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),    -   (18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group        (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy),    -   (20) an optionally halogenated C₁₋₆ alkylthio group,    -   (21) a 5- to 14-membered aromatic heterocyclic group,    -   (22) a 3- to 14-membered non-aromatic heterocyclic group,    -   (23) a formyl group,    -   (24) a carboxy group,    -   (25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,    -   (27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,    -   (28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl        group,    -   (29) a C₁₋₆ alkoxy-carbonyl group,    -   (32) a carbamoyl group,    -   (33) a thiocarbamoyl group,    -   (34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,    -   (36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group        (e.g., pyridylcarbamoyl, thienylcarbamoyl),    -   (37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl        group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl),    -   (38) an optionally halogenated C₁₋₆ alkylsulfonyl group,    -   (40) a 5- to 14-membered aromatic heterocyclylsulfonyl group        (e.g., pyridylsulfonyl, thienylsulfonyl),    -   (41) an optionally halogenated C₁₋₆ alkylsulfinyl group,    -   (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group        (e.g., pyridylsulfinyl, thienylsulfinyl),    -   (44) an amino group,    -   (45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino,        ethylamino, propylamino, isopropylamino, butylamino,        dimethylamino, diethylamino, dipropylamino, dibutylamino,        N-ethyl-N-methylamino),    -   (47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,        pyridylamino),    -   (49) a formylamino group,    -   (50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,        propanoylamino, butanoylamino),    -   (51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group (e.g.,        N-acetyl-N-methylamino),    -   (53) a C₁₋₆ alkoxy-carbonylamino group (e.g.,        methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,        butoxycarbonylamino, tert-butoxycarbonylamino),    -   (55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,        ethylsulfonylamino),    -   (57) an optionally halogenated C₁₋₆ alkyl group,    -   (58) a C₂₋₆ alkenyl group, and    -   (59) a C₂₋₆ alkynyl group.

In one embodiment, examples of the “optionally substituted sulfanyl(SH)group” for R⁴ include a sulfanyl group optionally having a substituentselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆alkyl-carbonyl group and a 5- to 14-membered aromatic heterocyclicgroup, each of which has 1 to 3 substituents selected from

-   -   (1) a halogen atom,    -   (2) a nitro group,    -   (3) a cyano group,    -   (4) an oxo group,    -   (5) a hydroxy group,    -   (6) an optionally halogenated C₁₋₆ alkoxy group,    -   (9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,        pyridyloxy),    -   (10) a 3- to 14-membered non-aromatic heterocyclyloxy group        (e.g., morpholinyloxy, piperidinyloxy),    -   (11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy,        propanoyloxy),    -   (13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,        ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),    -   (14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,        methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,        diethylcarbamoyloxy),    -   (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group        (e.g., nicotinoyloxy),    -   (17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy        group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),    -   (18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group        (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy),    -   (20) an optionally halogenated C₁₋₆ alkylthio group,    -   (21) a 5- to 14-membered aromatic heterocyclic group,    -   (22) a 3- to 14-membered non-aromatic heterocyclic group,    -   (23) a formyl group,    -   (24) a carboxy group,    -   (25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,    -   (27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,    -   (28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl        group,    -   (29) a C₁₋₆ alkoxy-carbonyl group,    -   (32) a carbamoyl group,    -   (33) a thiocarbamoyl group,    -   (34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,    -   (36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group        (e.g., pyridylcarbamoyl, thienylcarbamoyl),    -   (37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl        group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl),    -   (38) an optionally halogenated C₁₋₆ alkylsulfonyl group,    -   (40) a 5- to 14-membered aromatic heterocyclylsulfonyl group        (e.g., pyridylsulfonyl, thienylsulfonyl),    -   (41) an optionally halogenated C₁₋₆ alkylsulfinyl group,    -   (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group        (e.g., pyridylsulfinyl, thienylsulfinyl),    -   (44) an amino group,    -   (45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino,        ethylamino, propylamino, isopropylamino, butylamino,        dimethylamino, diethylamino, dipropylamino, dibutylamino,        N-ethyl-N-methylamino),    -   (47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,        pyridylamino),    -   (49) a formylamino group,    -   (50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,        propanoylamino, butanoylamino),    -   (51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group (e.g.,        N-acetyl-N-methylamino),    -   (53) a C₁₋₆ alkoxy-carbonylamino group (e.g.,        methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,        butoxycarbonylamino, tert-butoxycarbonylamino),    -   (55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,        ethylsulfonylamino),    -   (57) an optionally halogenated C₁₋₆ alkyl group,    -   (58) a C₂₋₆ alkenyl group, and    -   (59) a C₂₋₆ alkynyl group, and halogenated sulfanyl group.

In one embodiment, examples of the “optionally substituted silyl group”for R⁴ include a silyl group optionally having 1 to 3 substituentsselected from a C₁₋₆ alkyl group and a C₁₋₆ alkenyl group, each of whichhas 1 to 3 substituents selected from

-   -   (1) a halogen atom,    -   (2) a nitro group,    -   (3) a cyano group,    -   (4) an oxo group,    -   (5) a hydroxy group,    -   (6) an optionally halogenated C₁₋₆ alkoxy group,    -   (9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,        pyridyloxy),    -   (10) a 3- to 14-membered non-aromatic heterocyclyloxy group        (e.g., morpholinyloxy, piperidinyloxy),    -   (11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy,        propanoyloxy),    -   (13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,        ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),    -   (14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,        methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,        diethylcarbamoyloxy),    -   (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group        (e.g., nicotinoyloxy),    -   (17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy        group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),    -   (18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group        (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy),    -   (20) an optionally halogenated C₁₋₆ alkylthio group,    -   (21) a 5- to 14-membered aromatic heterocyclic group,    -   (22) a 3- to 14-membered non-aromatic heterocyclic group,    -   (23) a formyl group,    -   (24) a carboxy group,    -   (25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,    -   (27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,    -   (28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl        group,    -   (29) a C₁₋₆ alkoxy-carbonyl group,    -   (32) a carbamoyl group,    -   (33) a thiocarbamoyl group,    -   (34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,    -   (36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group        (e.g., pyridylcarbamoyl, thienylcarbamoyl),    -   (37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl        group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl),    -   (38) an optionally halogenated C₁₋₆ alkylsulfonyl group,    -   (40) a 5- to 14-membered aromatic heterocyclylsulfonyl group        (e.g., pyridylsulfonyl, thienylsulfonyl),    -   (41) an optionally halogenated C₁₋₆ alkylsulfinyl group,    -   (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group        (e.g., pyridylsulfinyl, thienylsulfinyl),    -   (44) an amino group,    -   (45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino,        ethylamino, propylamino, isopropylamino, butylamino,        dimethylamino, diethylamino, dipropylamino, dibutylamino,        N-ethyl-N-methylamino),    -   (47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,        pyridylamino),    -   (49) a formylamino group,    -   (50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,        propanoylamino, butanoylamino),    -   (51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group (e.g.,        N-acetyl-N-methylamino),    -   (53) a C₁₋₆ alkoxy-carbonylamino group (e.g.,        methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,        butoxycarbonylamino, tert-butoxycarbonylamino),    -   (55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,        ethylsulfonylamino),    -   (57) an optionally halogenated C₁₋₆ alkyl group,    -   (58) a C₂₋₆ alkenyl group, and    -   (59) a C₂₋₆ alkynyl group.        When the number of the substituents is 2 or more, the respective        substituents may be the same or different.

R⁴ is preferably

(1) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,isoxazolyl) optionally substituted by 1 to 3 hydroxy groups,(2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g.,dihydropyridyl (1,2-dihydropyridyl), pyrrolidinyl) optionallysubstituted by 1 to 3 oxo groups,(3) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, butyl, isobutyl,neo-pentyl) optionally substituted by 1 to 5 substituents selected from

-   -   (a) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolidinyl, piperidyl, imidazolidinyl,        pyrrolidinyl, oxazolidinyl, tetrahydropyrimidinyl        (1,2,3,4-tetrahydropyrimidinyl), dihydropyrimidinyl        (3,4-dihydropyrimidinyl), dihydropyridyl (1,2-dihydropyridyl),        1,1-dioxidotetrahydrothiopyranyl) optionally substituted by 1 to        5 substituents selected from        -   (i) an oxo group, and        -   (ii) a C₁₋₆ alkyl group (e.g., methyl),    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., isoxazolyl, oxadiazolyl (1,3,4-oxadiazolyl), pyridyl,        tetrazolyl) optionally substituted by 1 to 3 substituents        selected from        -   (i) a hydroxy group,        -   (ii) a C₁₋₆ alkyl group (e.g., methyl), and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),    -   (e) a carboxy group,    -   (f) a 8- to 14-membered fused polycyclic (preferably bi- or        tri-cyclic) aromatic heterocyclic group (e.g., indazolyl),    -   (g) a halogen atom (e.g., a fluorine atom),    -   (h) a cyano group, and    -   (i) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 carboxy groups,        (4) an amino group optionally mono- or di-substituted by 5- or        6-membered monocyclic aromatic heterocyclic group(s) (e.g.,        pyridazinyl, pyrazolyl) optionally substituted by 1 to 3 C₁₋₆        alkyl groups (e.g., methyl),        (5) a carboxy group, or        (6) a carbamoyl group.

R⁴ is more preferably

(1) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,isoxazolyl) optionally substituted by 1 to 3 hydroxy groups,(2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g.,dihydropyridyl (1,2-dihydropyridyl), pyrrolidinyl) optionallysubstituted by 1 to 3 oxo groups, or(3) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 5 substituents selected from

-   -   (a) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., dihydropyrimidinyl (3,4-dihydropyrimidinyl))        optionally substituted by 1 to 3 oxo groups,    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., isoxazolyl, oxadiazolyl (1,3,4-oxadiazolyl), pyridyl)        optionally substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group,        -   (ii) a C₁₋₆ alkyl group (e.g., methyl), and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (c) a hydroxy group.

In another embodiment, R⁴ is preferably

(1) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,isoxazolyl, pyrazolyl) optionally substituted by 1 to 5 (preferably 1 to3) substituents selected from

-   -   (a) a hydroxy group,    -   (b) a carboxy group, and    -   (c) a C₁₋₆ alkyl group (e.g., methyl),        (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., dihydropyridyl (1,2-dihydropyridyl), pyrrolidinyl,        azetidinyl, morpholinyl) optionally substituted by 1 to 3        substituents selected from    -   (a) an oxo group,    -   (b) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 substituents selected from        -   (i) a carboxy group, and        -   (ii) a C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl)            optionally substituted by 1 to 3 C₆₋₁₄ aryl groups (e.g.,            phenyl),    -   (c) a carboxy group,    -   (d) a hydroxy group, and    -   (e) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 carboxy groups,        (3) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, butyl,        isobutyl, sec-butyl, neo-pentyl, isopentyl) optionally        substituted by 1 to 5 (preferably 1 to 3) substituents selected        from    -   (a) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolidinyl, piperidyl, imidazolidinyl,        pyrrolidinyl, oxazolidinyl, tetrahydropyrimidinyl        (1,2,3,4-tetrahydropyrimidinyl), dihydropyrimidinyl        (3,4-dihydropyrimidinyl), dihydropyridyl (1,2-dihydropyridyl),        1,1-dioxidotetrahydrothiopyranyl, 1,1-dioxidothiadiazolidinyl        (1,1-dioxido-1,2,5-thiadiazolidinyl)) optionally substituted by        1 to 5 (preferably 1 to 3) substituents selected from        -   (i) an oxo group, and        -   (ii) a C₁₋₆ alkyl group (e.g., methyl),    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., isoxazolyl, oxadiazolyl (1,3,4-oxadiazolyl), pyridyl,        tetrazolyl) optionally substituted by 1 to 3 substituents        selected from        -   (i) a hydroxy group,        -   (ii) a C₁₋₆ alkyl group (e.g., methyl),        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy), and        -   (iv) a carboxy group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),    -   (e) a carboxy group,    -   (f) a 8- to 14-membered fused polycyclic (preferably bi- or        tri-cyclic) aromatic heterocyclic group (e.g., indazolyl),    -   (g) a halogen atom (e.g., a fluorine atom),    -   (h) a cyano group,    -   (i) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 carboxy groups,    -   (j) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl group(s) (e.g., methyl) optionally substituted by 1 to 3        carboxy groups, and    -   (k) a carbamoyl group,        (4) an amino group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridazinyl, pyrazolyl) optionally substituted by 1 to 3        C₁₋₆ alkyl groups (e.g., methyl), and    -   (b) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl)        optionally substituted by 1 to 3 substituents selected from        -   (i) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl,            ethoxycarbonyl) optionally substituted by 1 to 3 C₆₋₁₄ aryl            groups (e.g., phenyl), and        -   (ii) a carboxy group,            (5) a carboxy group,            (6) a carbamoyl group,            (7) a C₂₋₆ alkenyl group (e.g., vinyl) optionally            substituted by 1 to 3 carboxy groups,            (8) a C₁₋₆ alkyl-carbonyl group (e.g., propionyl) optionally            substituted by 1 to 3 carboxy groups, or            (9) a C₁₋₆ alkoxy group (e.g., ethoxy, propoxy) optionally            substituted by 1 to 3 carboxy groups.

R⁴ is more preferably

(1) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,isoxazolyl) optionally substituted by 1 to 3 hydroxy groups,(2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g.,dihydropyridyl (1,2-dihydropyridyl), pyrrolidinyl, azetidinyl)optionally substituted by 1 to 3 substituents selected from

-   -   (a) an oxo group, and    -   (b) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 carboxy groups,        (3) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, butyl,        isobutyl, neo-pentyl) optionally substituted by 1 to 5        (preferably 1 to 3) substituents selected from    -   (a) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolidinyl, dihydropyrimidinyl        (3,4-dihydropyrimidinyl)) optionally substituted by 1 to 3 oxo        groups,    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., isoxazolyl, oxadiazolyl (1,3,4-oxadiazolyl), pyridyl)        optionally substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group,        -   (ii) a C₁₋₆ alkyl group (e.g., methyl), and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (c) a hydroxy group,    -   (d) a carboxy group,    -   (e) a halogen atom (e.g., a fluorine atom),    -   (f) a cyano group, and    -   (g) a carbamoyl group,        (4) an amino group optionally mono- or di-substituted by        substituent(s) selected from a C₁₋₆ alkyl group (e.g., ethyl,        propyl) optionally substituted by 1 to 3 carboxy groups, or        (5) a C₂₋₆ alkenyl group (e.g., vinyl) optionally substituted by        1 to 3 carboxy groups.

R⁴ is still more preferably

(1) a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g.,azetidinyl) optionally substituted by 1 to 3 substituents selected froma C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 3carboxy groups, or(2) a C₁₋₆ alkyl group (e.g., propyl) optionally substituted by 1 to 3carboxy groups.

In another embodiment, R⁴ is preferably

(1) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, butyl, isobutyl,sec-butyl, neo-pentyl, isopentyl) optionally substituted by 1 to 3substituents selected from

-   -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a 5- to 6-membered monocyclic aromatic heterocyclic group        (e.g., isoxazolyl, oxadiazolyl (1,3,4-oxadiazolyl), pyridyl,        tetrazolyl),    -   (e) a 4- to 6-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolidinyl, piperidyl, imidazolidinyl,        pyrrolidinyl, oxazolidinyl, tetrahydropyrimidinyl        (1,2,3,4-tetrahydropyrimidinyl), dihydropyrimidinyl        (3,4-dihydropyrimidinyl), dihydropyridyl (1,2-dihydropyridyl),        1,1-dioxidotetrahydrothiopyranyl, 1,1-dioxidothiadiazolidinyl        (1,1-dioxido-1,2,5-thiadiazolidinyl)), and    -   (f) a carboxy group, or        (2) an optionally substituted heterocyclic group (e.g., a 5- or        6-membered monocyclic aromatic heterocyclic group (e.g.,        isoxazolyl), a 3- to 8-membered monocyclic non-aromatic        heterocyclic group (e.g., dihydropyridyl (1,2-dihydropyridyl),        pyrrolidinyl, azetidinyl, morpholinyl)).

R⁴ is more preferably

(1) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, butyl, isobutyl,sec-butyl, neo-pentyl, isopentyl) optionally substituted by 1 to 3substituents selected from

-   -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a 5- to 6-membered monocyclic aromatic heterocyclic group        (e.g., isoxazolyl, oxadiazolyl (1,3,4-oxadiazolyl), pyridyl,        tetrazolyl),    -   (e) a 4- to 6-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolidinyl, piperidyl, imidazolidinyl,        pyrrolidinyl, oxazolidinyl, tetrahydropyrimidinyl        (1,2,3,4-tetrahydropyrimidinyl), dihydropyrimidinyl        (3,4-dihydropyrimidinyl), dihydropyridyl (1,2-dihydropyridyl),        1,1-dioxidotetrahydrothiopyranyl, 1,1-dioxidothiadiazolidinyl        (1,1-dioxido-1,2,5-thiadiazolidinyl)), and    -   (f) a carboxy group,        (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., isoxazolyl) optionally substituted by 1 to 3 hydroxy        groups, or        (3) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., dihydropyridyl (1,2-dihydropyridyl), pyrrolidinyl,        azetidinyl) optionally substituted by 1 to 3 substituents        selected from    -   (a) an oxo group, and    -   (b) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 carboxy groups.

Examples of the above-mentioned “4- to 6-membered monocyclicnon-aromatic heterocyclic group” include a 4- to 6-membered monocyclicnon-aromatic heterocyclic group containing, as a ring-constituting atombesides carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom,a sulfur atom and an oxygen atom. Preferable examples of the “4- to6-membered monocyclic non-aromatic heterocyclic group” include thosesimilar to a 4- to 6-membered ring, from among the above-mentioned “3-to 8-membered monocyclic non-aromatic heterocyclic group”.

R¹³ is a substituent.

R¹³ is preferably an optionally substituted hydrocarbon group or anoptionally substituted amino group.

R¹³ is more preferably

(1) an amino group optionally mono- or di-substituted by substituent(s)selected from

-   -   (a) a C₁₋₆ alkoxy-carbonyl group (e.g., tert-butoxycarbonyl),        and    -   (b) a C₁₋₆ alkyl group (e.g., propyl) optionally substituted by        1 to 3 carboxy groups, or        (2) a C₁₋₆ alkyl group (e.g., propyl) optionally substituted by        1 to 3 substituents selected from a C₁₋₆ alkoxy-carbonyl group        (e.g., methoxycarbonyl).

Ring B is a benzene ring, a pyridine ring or a dihydropyridine ring,each of which is optionally further substituted.

Ring B is preferably a benzene ring, a pyridine ring or a1,2-dihydropyridine ring.

Ring B is more preferably a benzene ring or a pyridine ring.

In another embodiment, Ring B is preferably a benzene ring or a pyridinering, each of which is optionally further substituted.

Examples of the “additional substituent” of the “optionally furthersubstituted” for Ring B include the substituents selected from theabove-mentioned Substituent Group A. The number of the substituents is 1or 2. When the number of the substituents is 2, the respectivesubstituents may be the same or different.

The partial structure represented by the formula:

is CR^(5a)═CR⁶, CR^(5b)═N or C(═O)—NR⁷,

R^(5a) and R^(5b) are each independently an optionally substituted alkylgroup or an optionally substituted alkoxy group, and

R⁶ and R⁷ are each independently a hydrogen atom or a substituent.

In another embodiment, the partial structure represented by the formula:

is CR^(5a)═CR⁶, CR^(5b)═N or C(═O)—NR⁷,

R^(5a) and R^(5b) are each independently an optionally substituted alkylgroup, an optionally substituted alkoxy group, an optionally substitutedalkylsulfonyl group, a cyano group, an optionally substituted cyclicamino group or an oxetan-3-yloxy group, and

R⁶ and R⁷ are each independently a hydrogen atom or a substituent, or

the substituent that Ring B optionally further has and R^(5a) or R^(5b)in combination optionally form Ring D, wherein Ring D is a 5- or6-membered oxygen-containing heterocycle containing 1 to 2 oxygen atomsas heteroatoms in addition to carbon atoms, and is fused at the ringforming position, or

R^(5a) and R⁶ in combination optionally form Ring D′, wherein Ring D′ isa 5- or 6-membered oxygen-containing heterocycle containing 1 to 2oxygen atoms as heteroatoms in addition to carbon atoms, and is fused atthe ring forming position.

Examples of the “cyclic amino group” for R^(5a) and R^(5b) include a 3-to 14-membered (preferably 4- to 10-membered) cyclic amino group (whichis a group formed by removing one hydrogen atom from the nitrogen atom)optionally further containing, as a ring-constituting atom besidescarbon atoms and one nitrogen atom, 1 to 4 heteroatoms selected from anitrogen atom, a sulfur atom and an oxygen atom.

Preferable examples of the “cyclic amino group” include 4- to10-membered cyclic amino groups such as azetidino, pyrrolidino,imidazolidino, pyrazolidino, piperidino, piperazino, oxazolidino,isoxazolidino, thiazolidino, thiazolidino, morpholino, thiomorpholino,azepano and the like, and the like.

Examples of the “optionally substituted alkyl group” for R^(5a) orR^(5b) include a C₁₋₆ alkyl group optionally substituted bysubstituent(s) selected from the above-mentioned Substituent Group A.

Examples of the “optionally substituted alkoxy group” for R^(5a) orR^(5b) include a “C₁₋₆ alkoxy group” optionally substituted bysubstituent(s) selected from the above-mentioned Substituent Group A.

Examples of the “optionally substituted alkylsulfonyl group” for R^(5a)or R^(5b) include a “C₁₋₆ alkylsulfonyl group” optionally substituted bysubstituent(s) selected from the above-mentioned Substituent Group A.

Examples of the “optionally substituted cyclic amino group” for R^(5a)or R^(5b) include a “cyclic amino group” optionally substituted bysubstituent(s) selected from the above-mentioned Substituent Group A.

The number of the above-mentioned substituents in the “optionallysubstituted alkyl group”, “optionally substituted alkoxy group”,“optionally substituted alkylsulfonyl group” and “optionally substitutedcyclic amino group” is, for example, 1 to 5, preferably 1 to 3. When thenumber of the substituents is 2 or more, the respective substituents maybe the same or different.

In another embodiment, examples of the “optionally substituted alkoxygroup” for R^(5d) or R^(5b) include a group represented by the formula:—OR⁹ wherein R⁹ is an optionally substituted C₁₋₆ alkyl group.

Examples of the “5- or 6-membered oxygen-containing heterocycle” forRing D or Ring D′ include a 5- or 6-membered unsaturated non-aromaticheterocyclic group or a 5-membered aromatic heterocyclic group, each ofwhich optionally further contains, as a ring-constituting atom besidescarbon atoms and 1 to 2 oxygen atoms, 1 to 2 heteroatoms selected from asulfur atom and a nitrogen atom.

Preferable examples of the “5- or 6-membered oxygen-containingheterocycle” include 5- or 6-membered unsaturated non-aromaticheterocyclic groups such as dihydrofuran (e.g., 2,3-dihydrofuran,2,5-dihydrofuran), dioxole (e.g., 1,3-dioxole), dihydrooxazole (e.g.,2,3-dihydrooxazole), dihydroisoxazole (e.g., 2,3-dihydroisoxazole),pyran (e.g., 2H-pyran), dihydropyran (e.g., 3,4-dihydro-2H-pyran),dihydrodioxin (e.g., 2,3-dihydro-1,4-dioxin) and the like; 5-memberedaromatic heterocyclic groups such as furan, oxazole, isoxazole and thelike.

In the partial structure represented by the formula:

X¹ and X² are present in this order starting from the left, and they arenot revised. The same applies to CR^(5a)═CR⁶, CR^(5b)═N and C(═O)—NR⁷.

The partial structure represented by the formula:

is preferably CR^(5a)═CR⁶, CR^(5b)═N or C(═O)—NR⁷; and

R^(5a) and R^(5b) are each independently a C₁₋₆ alkyl group (e.g.,methyl) optionally substituted by 1 to 3 C₁₋₆ alkoxy groups (e.g.,methoxy, ethoxy), or a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy);

R⁶ is a hydrogen atom; and

R⁷ is a C₁₋₆ alkyl group (e.g., methyl).

The partial structure represented by the formula:

is more preferably CR^(5a)═CR⁶ or CR⁵═N; and

R^(5a) is a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1to 3 C₁₋₆ alkoxy groups (e.g., methoxy, ethoxy), or a C₁₋₆ alkoxy group(e.g., methoxy, ethoxy);

R^(5b) is a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy); and

R⁶ is a hydrogen atom.

In another embodiment, the partial structure represented by the formula:

is preferably CR^(5a)═CR⁶ or CR^(5b)═N.

R^(5a) and R^(5b) are preferably each independently

(1) a C₁₋₆ alkyl group (e.g., methyl, propyl, isopropyl) optionallysubstituted by 1 to 3 substituents selected from a C₁₋₆ alkoxy group(e.g., methoxy) optionally substituted by 1 to 3 halogen atoms (e.g., afluorine atom),(2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy)optionally substituted by 1 to 3 substituents selected from

-   -   (a) a halogen atom (e.g., a fluorine atom), and    -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),        (3) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),        (4) a cyano group,        (5) a cyclic amino group (e.g., azetidino) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), or        (6) an oxetan-3-yloxy group.

R^(5a) and R^(5b) are more preferably each independently

(1) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 3C₁₋₆ alkoxy groups (e.g., methoxy),(2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) optionally substitutedby 1 to 3 halogen atoms (e.g., a fluorine atom), or(3) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl).

R^(5a) and R^(5b) are still more preferably each independently a C₁₋₆alkoxy group (e.g., methoxy).

In another embodiment, R^(5a) is preferably

(1) a C₁₋₆ alkyl group (e.g., methyl, propyl) optionally substituted by1 to 3 substituents selected from a C₁₋₆ alkoxy group (e.g., methoxy)optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),(2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy)optionally substituted by 1 to 3 substituents selected from

-   -   (a) a halogen atom (e.g., a fluorine atom), and    -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),        (3) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),        (4) a cyano group,        (5) a cyclic amino group (e.g., azetidino) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), or        (6) an oxetan-3-yloxy group.

R^(5a) is more preferably

(1) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 3C₁₋₆ alkoxy groups (e.g., methoxy),(2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) optionally substitutedby 1 to 3 halogen atoms (e.g., a fluorine atom), or(3) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl).

In another embodiment, R^(5a) is preferably

(1) an optionally substituted C₁₋₆ alkyl group,(2) an optionally substituted C₁₋₆ alkoxy group, or(3) an optionally substituted C₁₋₆ alkylsulfonyl group.

Examples of the “optionally substituted C₁₋₆ alkyl group” include a“C₁₋₆ alkyl group” optionally substituted by substituent(s) selectedfrom the above-mentioned Substituent Group A.

Examples of the “optionally substituted C₁₋₆ alkoxy group” include a“C₁₋₆ alkoxy group” optionally substituted by substituent(s) selectedfrom the above-mentioned Substituent Group A.

Examples of the “optionally substituted C₁₋₆ alkylsulfonyl group”include a “C₁₋₆ alkylsulfonyl group” optionally substituted bysubstituent(s) selected from the above-mentioned Substituent Group A.

The number of the above-mentioned substituents in the “optionallysubstituted C₁₋₆ alkyl group”, “optionally substituted C₁₋₆ alkoxygroup” and “optionally substituted C₁₋₆ alkylsulfonyl group” is, forexample, 1 to 5, preferably 1 to 3. When the number of the substituentsis 2 or more, the respective substituents may be the same or different.

R^(5b) is preferably

(1) a C₁₋₆ alkyl group (e.g., methyl, propyl, isopropyl) optionallysubstituted by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy), or(2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) optionally substitutedby 1 to 3 halogen atoms (e.g., a fluorine atom).

R^(5b) is more preferably

(1) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 3C₁₋₆ alkoxy groups (e.g., methoxy), or(2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy).

R^(5b) is still more preferably a C₁₋₆ alkoxy group (e.g., methoxy).

In another embodiment, R^(5b) is preferably

(1) an optionally substituted C₁₋₄ alkoxy group, or(2) an optionally substituted C₁₋₄ alkyl group.

Specific examples of the “C₁₋₄ alkoxy group” of the “optionallysubstituted C₁₋₄ alkoxy group” for R^(5b) include methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.

Specific examples of the “C₁₋₄ alkyl group” of the “optionallysubstituted C₁₋₄ alkyl group” for R^(5b) include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

Examples of the “optionally substituted C₁₋₄ alkoxy group” include a“C₁₋₄ alkoxy group” optionally substituted by substituent(s) selectedfrom the above-mentioned Substituent Group A.

Examples of the “optionally substituted C₁₋₄ alkyl group” include a“C₁₋₄ alkyl group” optionally substituted by substituent(s) selectedfrom the above-mentioned Substituent Group A.

The number of the above-mentioned substituents in the “optionallysubstituted C₁₋₄ alkoxy group” and “optionally substituted C₁₋₄ alkylgroup” is, for example, 1 to 5, preferably 1 to 3. When the number ofthe substituents is 2 or more, the respective substituents may be thesame or different.

R⁶ is preferably a hydrogen atom or an optionally substitutedhydrocarbon group.

R⁶ is more preferably a hydrogen atom or a C₁₋₆ alkyl group (e.g.,methyl).

R⁶ is still more preferably a hydrogen atom.

R⁷ is preferably a hydrogen atom or an optionally substitutedhydrocarbon group.

R⁷ is more preferably a C₁₋₆ alkyl group (e.g., methyl).

Preferably, the substituent that Ring B optionally further has andR^(5a) or R^(5b) in combination optionally form Ring D wherein the RingD is a dihydrofuran ring (e.g., 2,3-dihydrofuran) and is fused at thering forming position.

Preferably, R^(5a) and R⁶ in combination optionally form Ring D′ whereinRing D′ is a dihydrofuran ring (e.g., 2,3-dihydrofuran), a dioxole ring(e.g., 1,3-dioxole) or a dihydrodioxin ring (e.g.,2,3-dihydro-1,4-dioxin), and each is fused at the ring forming position.

More preferably, R^(5a) and R⁶ in combination optionally form Ring D′wherein Ring D′ is a dioxole ring (e.g., 1,3-dioxole), and is fused atthe ring forming position.

In another embodiment, the partial structure represented by the formula:

is preferably CR^(5a)═CR⁶, CR^(5b)═N or C(═O)—NR⁷,

R^(5a) and R^(5b) are each independently

(1) a C₁₋₆ alkyl group (e.g., methyl, propyl, isopropyl) optionallysubstituted by 1 to 3 substituents selected from a C₁₋₆ alkoxy group(e.g., methoxy) optionally substituted by 1 to 3 halogen atoms (e.g., afluorine atom),(2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy)optionally substituted by 1 to 3 substituents selected from

-   -   (a) a halogen atom (e.g., a fluorine atom), and    -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),        (3) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),        (4) a cyano group,        (5) a cyclic amino group (e.g., azetidino) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), or        (6) an oxetan-3-yloxy group,

R⁶ is a hydrogen atom or a C₁₋₆ alkyl group (e.g., methyl), and

R⁷ is a C₁₋₆ alkyl group (e.g., methyl), or

the substituent that Ring B optionally further has and R^(5a) or R^(5b)in combination optionally form Ring D wherein the Ring D is adihydrofuran ring (e.g., 2,3-dihydrofuran) and is fused at the ringforming position, or

R^(5a) and R⁶ in combination optionally form Ring D′ wherein Ring D′ isa dihydrofuran ring (e.g., 2,3-dihydrofuran), a dioxole ring (e.g.,1,3-dioxole) or a dihydrodioxin ring (e.g., 2,3-dihydro-1,4-dioxin), andeach is fused at the ring forming position.

The partial structure represented by the formula:

is more preferably CR^(5a)═CR⁶ or CR^(5b)═N,

R^(5a) and R^(5b) are each independently

(1) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 3C₁₋₆ alkoxy groups (e.g., methoxy),(2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) optionally substitutedby 1 to 3 halogen atoms (e.g., a fluorine atom), or(3) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl), and

R⁶ is a hydrogen atom, or

R^(5a) and R⁶ in combination optionally form Ring D′ wherein Ring D′ isa dioxole ring (e.g., 1,3-dioxole), and is fused at the ring formingposition.

The partial structure represented by the formula:

is still more preferably CR^(5a)═CR⁶ or CR^(5b)═N;

R^(5a) and R^(5b) are each independently a C₁₋₆ alkoxy group (e.g.,methoxy), and

R¹ is a hydrogen atom, or

R^(5a) and R⁶ in combination optionally form Ring D′ wherein Ring D′ isa dioxole ring (e.g., 1,3-dioxole), and is fused at the ring formingposition.

In another embodiment, the partial structure represented by the formula:

is preferably CR^(5a)═CR⁶, CR^(5b)═N or C(═O)—NR⁷,

R⁵ is

(1) a C₁₋₆ alkyl group (e.g., methyl, propyl) optionally substituted by1 to 3 substituents selected from a C₁₋₆ alkoxy group (e.g., methoxy)optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),(2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy)optionally substituted by 1 to 3 substituents selected from

-   -   (a) a halogen atom (e.g., a fluorine atom), and    -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),        (3) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),        (4) a cyano group,        (5) a cyclic amino group (e.g., azetidino) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), or

(6) an oxetan-3-yloxy group,

R^(5b) is

(1) a C₁₋₆ alkyl group (e.g., methyl, propyl, isopropyl) optionallysubstituted by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy), or(2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) optionally substitutedby 1 to 3 halogen atoms (e.g., a fluorine atom),

R⁶ is a hydrogen atom or a C₁₋₆ alkyl group (e.g., methyl), and

R⁷ is a C₁₋₆ alkyl group (e.g., methyl), or

the substituent that Ring B optionally further has and R^(5a) or R^(5b)in combination optionally form Ring D wherein the Ring D is adihydrofuran ring (e.g., 2,3-dihydrofuran) and is fused at the ringforming position, or

R^(5a) and R⁶ in combination optionally form Ring D′ wherein Ring D′ isa dihydrofuran ring (e.g., 2,3-dihydrofuran), a dioxole ring (e.g.,1,3-dioxole) or a dihydrodioxin ring (e.g., 2,3-dihydro-1,4-dioxin), andeach is fused at the ring forming position.

The partial structure represented by the formula:

is more preferably CR^(5a)═CR⁶ or CR^(5b)═N,

R^(5a) is

(1) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 3C₁₋₆ alkoxy groups (e.g., methoxy),(2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) optionally substitutedby 1 to 3 halogen atoms (e.g., a fluorine atom), or(3) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),

R^(5b) is

(1) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 3C₁₋₆ alkoxy groups (e.g., methoxy), or(2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy), and

R⁶ is a hydrogen atom, or

R^(5a) and R⁶ in combination optionally form Ring D′ wherein Ring D′ isa dioxole ring (e.g., 1,3-dioxole), and is fused at the ring formingposition.

In the formula (I), the partial structure represented by the formula:

wherein each symbol is as defined above,encompasses the partial structure selected from the formulas:

wherein each symbol is as defined above.

In one embodiment, it is preferably the partial structure selected fromthe formulas:

wherein each symbol is as defined above,more preferably the partial structure selected from the formulas:

wherein each symbol is as defined above.

Specific examples of the partial structure represented by the formula:

wherein each symbol is as defined above,include the partial structure represented by the formula:

wherein each symbol is as defined above.

Specific examples of the partial structure represented by the formula:

wherein each symbol is as defined above,include the partial structure selected from the formulas:

wherein each symbol is as defined above.

Y is an optionally substituted methylene group or an oxygen atom.

Examples of the “optionally substituted methylene group” include a“methylene group” optionally substituted by substituent(s) selected fromthe above-mentioned Substituent Group A.

Y is preferably a methylene group or an oxygen atom, more preferably amethylene group.

W is an optionally substituted C₁₋₂ alkylene group.

Examples of the “optionally substituted C₁₋₂ alkylene group” include a“C₁₋₂ alkylene group” optionally substituted by substituent(s) selectedfrom the above-mentioned Substituent Group A.

W is preferably a C₁₋₂ alkylene group (e.g., methylene, ethylene(—CH₂—CH₂—)), more preferably a methylene group.

In one embodiment, in formula (I) or formula (Ia), the partial structurerepresented by the formula —Y—W— is preferably —CH₂—CH₂— or —O—CH₂—CH₂—,more preferably —CH₂—CH₂—.

Preferable examples of the ring, group, substituent and the likeexplained in the present specification are more preferably used incombination.

Preferable examples of compound (I) include the following compounds.

[Compound I-A1]

A compound wherein

Ring A is a 6-membered aromatic ring (e.g., a benzene ring, a pyridinering) optionally further substituted by 1 to 3 (preferably 1 or 2)substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (3) a cyano group;

R¹ is

(1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))

-   -   wherein    -   Q is a carbon atom or a silicon atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy, ethoxy)        optionally substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (b) a C₁₋₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl),    -   (c) a carbamoyl group optionally mono- or di-substituted by        substituent(s) selected from        -   (i) a C₁₋₆ alkyl group (e.g., ethyl), and        -   (ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),    -   (d) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., oxadiazolyl (1,3,4-oxadiazolyl)) optionally substituted        by 1 to 3 C₁₋₆ alkyl groups (e.g., methyl), or    -   (e) a 3- to 8-membered monocyclic non-aromatic        heterocyclylcarbonyl group (e.g., pyrrolidinylcarbonyl), or        R^(1c) is bonded to one substituent for Ring A to form    -   (a) a C₃₋₁₀ cycloalkene ring (e.g., cyclopentene), or    -   (b) a 3- to 14-membered non-aromatic heterocycle (e.g.,        dihydrofuran), or        (2) a neo-pentyl group;

R¹¹ is —CR¹²R^(12′)—R^(12″), —C(═O)—R⁴ or —SO₂—R¹³;

R¹² is a C₁₋₆ alkyl group (e.g., ethyl) optionally substituted by 1 to 3C₁₋₆ alkoxy-carbonyl groups (e.g., methoxycarbonyl), and R^(12′) andR^(12″) are hydrogen atoms;

R⁴ is

(1) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,isoxazolyl, pyrazolyl) optionally substituted by 1 to 5 (preferably 1 to3) substituents selected from

-   -   (a) a hydroxy group,    -   (b) a carboxy group, and    -   (c) a C₁₋₆ alkyl group (e.g., methyl),        (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., dihydropyridyl (1,2-dihydropyridyl), pyrrolidinyl,        azetidinyl, morpholinyl) optionally substituted by 1 to 3        substituents selected from    -   (a) an oxo group,    -   (b) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 substituents selected from        -   (i) a carboxy group, and        -   (ii) a C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl)            optionally substituted by 1 to 3 C₆₋₁₄ aryl groups (e.g.,            phenyl),    -   (c) a carboxy group,    -   (d) a hydroxy group, and    -   (e) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 carboxy groups,        (3) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, butyl,        isobutyl, sec-butyl, neo-pentyl, isopentyl) optionally        substituted by 1 to 5 (preferably 1 to 3) substituents selected        from    -   (a) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolidinyl, piperidyl, imidazolidinyl,        pyrrolidinyl, oxazolidinyl, tetrahydropyrimidinyl        (1,2,3,4-tetrahydropyrimidinyl), dihydropyrimidinyl        (3,4-dihydropyrimidinyl), dihydropyridyl (1,2-dihydropyridyl),        1,1-dioxidotetrahydrothiopyranyl, 1,1-dioxidothiadiazolidinyl        (1,1-dioxido-1,2,5-thiadiazolidinyl)) optionally substituted by        1 to 5 (preferably 1 to 3) substituents selected from        -   (i) an oxo group, and        -   (ii) a C₁₋₆ alkyl group (e.g., methyl),    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., isoxazolyl, oxadiazolyl (1,3,4-oxadiazolyl), pyridyl,        tetrazolyl) optionally substituted by 1 to 3 substituents        selected from        -   (i) a hydroxy group,        -   (ii) a C₁₋₆ alkyl group (e.g., methyl),        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy), and        -   (iv) a carboxy group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),    -   (e) a carboxy group,    -   (f) a 8- to 14-membered fused polycyclic (preferably bi- or        tri-cyclic) aromatic heterocyclic group (e.g., indazolyl),    -   (g) a halogen atom (e.g., a fluorine atom),    -   (h) a cyano group,    -   (i) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 carboxy groups,    -   (j) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl group(s) (e.g., methyl) optionally substituted by 1 to 3        carboxy groups, and    -   (k) a carbamoyl group,        (4) an amino group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridazinyl, pyrazolyl) optionally substituted by 1 to 3        C₁₋₆ alkyl groups (e.g., methyl), and    -   (b) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl)        optionally substituted by 1 to 3 substituents selected from        -   (i) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl,            ethoxycarbonyl) optionally substituted by 1 to 3 C₆₋₁₄ aryl            groups (e.g., phenyl), and        -   (ii) a carboxy group,            (5) a carboxy group,            (6) a carbamoyl group,            (7) a C₂₋₆ alkenyl group (e.g., vinyl) optionally            substituted by 1 to 3 carboxy groups,            (8) a C₁₋₆ alkyl-carbonyl group (e.g., propionyl) optionally            substituted by 1 to 3 carboxy groups, or            (9) a C₁₋₆ alkoxy group (e.g., ethoxy, propoxy) optionally            substituted by 1 to 3 carboxy groups;

R¹³ is

(1) an amino group optionally mono- or di-substituted by substituent(s)selected from

-   -   (a) a C₁₋₆ alkoxy-carbonyl group (e.g., tert-butoxycarbonyl),        and    -   (b) a C₁₋₆ alkyl group (e.g., propyl) optionally substituted by        1 to 3 carboxy groups, or        (2) a C₁₋₆ alkyl group (e.g., propyl) optionally substituted by        1 to 3 substituents selected from a C₁₋₆ alkoxy-carbonyl group        (e.g., methoxycarbonyl);

Ring B is a benzene ring, a pyridine ring or a dihydropyridine ring,each of which is optionally further substituted;

the partial structure represented by the formula:

is CR^(5a)═CR⁶, CR^(5b)═N or C(═O)—NR⁷; and

R^(5a) and R^(5b) are each independently

(1) a C₁₋₆ alkyl group (e.g., methyl, propyl, isopropyl) optionallysubstituted by 1 to 3 substituents selected from a C₁₋₆ alkoxy group(e.g., methoxy) optionally substituted by 1 to 3 halogen atoms (e.g., afluorine atom),(2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy)optionally substituted by 1 to 3 substituents selected from

-   -   (a) a halogen atom (e.g., a fluorine atom), and    -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),        (3) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),        (4) a cyano group,        (5) a cyclic amino group (e.g., azetidino) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), or        (6) an oxetan-3-yloxy group;

R⁶ is a hydrogen atom or a C₁₋₆ alkyl group (e.g., methyl); and

R⁷ is a C₁₋₆ alkyl group (e.g., methyl); or

the substituent that Ring B optionally further has and R^(5a) or R^(5b)in combination optionally form Ring D wherein the Ring D is adihydrofuran ring (e.g., 2,3-dihydrofuran) and is fused at the ringforming position; or

R^(5a) and R⁶ in combination optionally form Ring D′ wherein Ring D′ isa dihydrofuran ring (e.g., 2,3-dihydrofuran), a dioxole ring (e.g.,1,3-dioxole) or a dihydrodioxin ring (e.g., 2,3-dihydro-1,4-dioxin), andeach is fused at the ring forming position;

Y is a methylene group or an oxygen atom; and

W is a C₁₋₂ alkylene group (e.g., methylene, ethylene (—CH₂—CH₂—))

or a salt thereof.

[Compound I-A2]

A compound wherein

Ring A is a 6-membered aromatic ring (e.g., a benzene ring, a pyridinering) optionally further substituted by 1 to 3 (preferably 1 or 2)substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (3) a cyano group;

R¹ is

(1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))

-   -   wherein    -   Q is a carbon atom or a silicon atom,    -   R^(1a) and R^(1b) are each independently a C₁₋₆ alkyl group        (e.g., methyl), and    -   R^(1c) is    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy, ethoxy)        optionally substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (b) a C₁₋₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl),    -   (c) a carbamoyl group optionally mono- or di-substituted by        substituent(s) selected from        -   (i) a C₁₋₆ alkyl group (e.g., ethyl), and        -   (ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),    -   (d) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., oxadiazolyl (1,3,4-oxadiazolyl)) optionally substituted        by 1 to 3 C₁₋₆ alkyl groups (e.g., methyl), or    -   (e) a 3- to 8-membered monocyclic non-aromatic        heterocyclylcarbonyl group (e.g., pyrrolidinylcarbonyl), or        R^(1c) is bonded to one substituent for Ring A to form    -   (a) a C₃₋₁₀ cycloalkene ring (e.g., cyclopentene), or    -   (b) a 3- to 14-membered non-aromatic heterocycle (e.g.,        dihydrofuran), or        (2) a neo-pentyl group;

R¹¹ is —CR¹²R^(12′)—R^(12″), —C(═O)—R⁴ or —SO₂—R¹³;

R¹² is a C₁₋₆ alkyl group (e.g., ethyl) optionally substituted by 1 to 3C₁₋₆ alkoxy-carbonyl groups (e.g., methoxycarbonyl), and R^(12′) andR^(12″) are hydrogen atoms;

R⁴ is

(1) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,isoxazolyl, pyrazolyl) optionally substituted by 1 to 5 (preferably 1 to3) substituents selected from

-   -   (a) a hydroxy group,    -   (b) a carboxy group, and    -   (c) a C₁₋₆ alkyl group (e.g., methyl),        (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., dihydropyridyl (1,2-dihydropyridyl), pyrrolidinyl,        azetidinyl, morpholinyl) optionally substituted by 1 to 3        substituents selected from    -   (a) an oxo group,    -   (b) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 substituents selected from        -   (i) a carboxy group, and        -   (ii) a C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl)            optionally substituted by 1 to 3 C₆₋₁₄ aryl groups (e.g.,            phenyl),    -   (c) a carboxy group,    -   (d) a hydroxy group, and    -   (e) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 carboxy groups,        (3) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, butyl,        isobutyl, sec-butyl, neo-pentyl, isopentyl) optionally        substituted by 1 to 5 (preferably 1 to 3) substituents selected        from    -   (a) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolidinyl, piperidyl, imidazolidinyl,        pyrrolidinyl, oxazolidinyl, tetrahydropyrimidinyl        (1,2,3,4-tetrahydropyrimidinyl), dihydropyrimidinyl        (3,4-dihydropyrimidinyl), dihydropyridyl (1,2-dihydropyridyl),        1,1-dioxidotetrahydrothiopyranyl, 1,1-dioxidothiadiazolidinyl        (1,1-dioxido-1,2,5-thiadiazolidinyl)) optionally substituted by        1 to 5 (preferably 1 to 3) substituents selected from        -   (i) an oxo group, and        -   (ii) a C₁₋₆ alkyl group (e.g., methyl),    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., isoxazolyl, oxadiazolyl (1,3,4-oxadiazolyl), pyridyl,        tetrazolyl) optionally substituted by 1 to 3 substituents        selected from        -   (i) a hydroxy group,        -   (ii) a C₁₋₆ alkyl group (e.g., methyl),        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy), and        -   (iv) a carboxy group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),    -   (e) a carboxy group,    -   (f) a 8- to 14-membered fused polycyclic (preferably bi- or        tri-cyclic) aromatic heterocyclic group (e.g., indazolyl),    -   (g) a halogen atom (e.g., a fluorine atom),    -   (h) a cyano group,    -   (i) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 carboxy groups,    -   (j) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl group(s) (e.g., methyl) optionally substituted by 1 to 3        carboxy groups, and    -   (k) a carbamoyl group,        (4) an amino group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridazinyl, pyrazolyl) optionally substituted by 1 to 3        C₁₋₆ alkyl groups (e.g., methyl), and    -   (b) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl)        optionally substituted by 1 to 3 substituents selected from        -   (i) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl,            ethoxycarbonyl) optionally substituted by 1 to 3 C₆₋₁₄ aryl            groups (e.g., phenyl), and        -   (ii) a carboxy group,            (5) a carboxy group,            (6) a carbamoyl group,            (7) a C₂₋₆ alkenyl group (e.g., vinyl) optionally            substituted by 1 to 3 carboxy groups,            (8) a C₁₋₆ alkyl-carbonyl group (e.g., propionyl) optionally            substituted by 1 to 3 carboxy groups, or            (9) a C₁₋₆ alkoxy group (e.g., ethoxy, propoxy) optionally            substituted by 1 to 3 carboxy groups;

R¹³ is

(1) an amino group optionally mono- or di-substituted by substituent(s)selected from

-   -   (a) a C₁₋₆ alkoxy-carbonyl group (e.g., tert-butoxycarbonyl),        and    -   (b) a C₁₋₆ alkyl group (e.g., propyl) optionally substituted by        1 to 3 carboxy groups, or        (2) a C₁₋₆ alkyl group (e.g., propyl) optionally substituted by        1 to 3 substituents selected from a C₁₋₆ alkoxy-carbonyl group        (e.g., methoxycarbonyl);

Ring B is a benzene ring, a pyridine ring or a dihydropyridine ring,each of which is optionally further substituted;

the partial structure represented by the formula:

is CR^(5a)═CR⁶, CR^(5b)═N or C(═O)—NR⁷; and

R^(5a) is

(1) a C₁₋₆ alkyl group (e.g., methyl, propyl) optionally substituted by1 to 3 substituents selected from a C₁₋₆ alkoxy group (e.g., methoxy)optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),(2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy)optionally substituted by 1 to 3 substituents selected from

-   -   (a) a halogen atom (e.g., a fluorine atom), and    -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),        (3) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),        (4) a cyano group,        (5) a cyclic amino group (e.g., azetidino) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), or        (6) an oxetan-3-yloxy group;

R^(5b) is

(1) a C₁₋₆ alkyl group (e.g., methyl, propyl, isopropyl) optionallysubstituted by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy), or(2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) optionally substitutedby 1 to 3 halogen atoms (e.g., a fluorine atom);

R⁶ is a hydrogen atom or a C₁₋₆ alkyl group (e.g., methyl); and

R⁷ is a C₁₋₆ alkyl group (e.g., methyl); or

the substituent that Ring B optionally further has and R^(5a) or R^(5b)in combination optionally form Ring D wherein the Ring D is adihydrofuran ring (e.g., 2,3-dihydrofuran) and is fused at the ringforming position; or

R^(5a) and R⁶ in combination optionally form Ring D′ wherein Ring D′ isa dihydrofuran ring (e.g., 2,3-dihydrofuran), a dioxole ring (e.g.,1,3-dioxole) or a dihydrodioxin ring (e.g., 2,3-dihydro-1,4-dioxin), andeach is fused at the ring forming position;

Y is a methylene group or an oxygen atom; and

W is a C₁₋₂ alkylene group (e.g., methylene, ethylene (—CH₂—CH₂—))

or a salt thereof.

[Compound I-B1]

A compound wherein

Ring A is a benzene ring optionally further substituted by 1 to 3(preferably 1 or 2) substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (2) a cyano group;

R¹ is a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))

-   -   wherein    -   Q is a carbon atom or a silicon atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy, ethoxy)        optionally substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (b) a C₁₋₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl), or    -   (c) a 3- to 8-membered monocyclic non-aromatic        heterocyclylcarbonyl group (e.g., pyrrolidinylcarbonyl), or        R^(1c) is bonded to one substituent for Ring A to form a C₃₋₁₀        cycloalkene ring (e.g., cyclopentene);

R¹¹ is —C(═O)—R⁴;

R⁴ is

(1) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,isoxazolyl) optionally substituted by 1 to 3 hydroxy groups,(2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g.,dihydropyridyl (1,2-dihydropyridyl), pyrrolidinyl, azetidinyl)optionally substituted by 1 to 3 substituents selected from

-   -   (a) an oxo group, and    -   (b) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 carboxy groups,        (3) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, butyl,        isobutyl, neo-pentyl) optionally substituted by 1 to 5        (preferably 1 to 3) substituents selected from    -   (a) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolidinyl, dihydropyrimidinyl        (3,4-dihydropyrimidinyl)) optionally substituted by 1 to 3 oxo        groups,    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., isoxazolyl, oxadiazolyl (1,3,4-oxadiazolyl), pyridyl)        optionally substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group,        -   (ii) a C₁₋₆ alkyl group (e.g., methyl), and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (c) a hydroxy group,    -   (d) a carboxy group,    -   (e) a halogen atom (e.g., a fluorine atom),    -   (f) a cyano group, and    -   (g) a carbamoyl group,        (4) an amino group optionally mono- or di-substituted by        substituent(s) selected from a C₁₋₆ alkyl group (e.g., ethyl,        propyl) optionally substituted by 1 to 3 carboxy groups, or        (5) a C₂₋₆ alkenyl group (e.g., vinyl) optionally substituted by        1 to 3 carboxy groups;

the partial structure represented by the formula:

is CR^(5a)═CR⁶ or CR^(5b)═N, and

R^(5a) and R^(5b) are each independently

(1) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 3C₁₋₆ alkoxy groups (e.g., methoxy),(2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) optionally substitutedby 1 to 3 halogen atoms (e.g., a fluorine atom), or(3) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl); and

R⁶ is a hydrogen atom; or

R^(5a) and R⁶ in combination optionally form Ring D′ wherein Ring D′ isa dioxole ring (e.g., 1,3-dioxole), and is fused at the ring formingposition;

Y is a methylene group or an oxygen atom; and

W is a C₁₋₂ alkylene group (e.g., methylene, ethylene (—CH₂—CH₂—))

or a salt thereof.

[Compound I-B2]

A compound wherein

Ring A is a benzene ring optionally further substituted by 1 to 3(preferably 1 or 2) substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (2) a cyano group;

R¹ is a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))

-   -   wherein    -   Q is a carbon atom or a silicon atom,    -   R^(1a) and R^(1b) are each independently a C₁₋₆ alkyl group        (e.g., methyl), and    -   R^(1c) is    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy, ethoxy)        optionally substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom),        -   (ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (b) a C₁₋₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl), or    -   (c) a 3- to 8-membered monocyclic non-aromatic        heterocyclylcarbonyl group (e.g., pyrrolidinylcarbonyl), or        R^(1c) is bonded to one substituent for Ring A to form a C₃₋₁₀        cycloalkene ring (e.g., cyclopentene);

R¹¹ is —C(═O)—R⁴;

R⁴ is

(1) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,isoxazolyl) optionally substituted by 1 to 3 hydroxy groups,(2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g.,dihydropyridyl (1,2-dihydropyridyl), pyrrolidinyl, azetidinyl)optionally substituted by 1 to 3 substituents selected from

(a) an oxo group, and

(b) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 3carboxy groups,

(3) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, butyl, isobutyl,neo-pentyl) optionally substituted by 1 to 5 (preferably 1 to 3)substituents selected from

-   -   (a) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolidinyl, dihydropyrimidinyl        (3,4-dihydropyrimidinyl)) optionally substituted by 1 to 3 oxo        groups,    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., isoxazolyl, oxadiazolyl (1,3,4-oxadiazolyl), pyridyl)        optionally substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group,        -   (ii) a C₁₋₆ alkyl group (e.g., methyl), and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (c) a hydroxy group,    -   (d) a carboxy group,    -   (e) a halogen atom (e.g., a fluorine atom),    -   (f) a cyano group, and    -   (g) a carbamoyl group,        (4) an amino group optionally mono- or di-substituted by        substituent(s) selected from a C₁₋₆ alkyl group (e.g., ethyl,        propyl) optionally substituted by 1 to 3 carboxy groups, or        (5) a C₂₋₆ alkenyl group (e.g., vinyl) optionally substituted by        1 to 3 carboxy groups;

the partial structure represented by the formula:

is CR^(5a)═CR⁶ or CR^(5b)═N; and

R^(5a) is

(1) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 3C₁₋₆ alkoxy groups (e.g., methoxy),(2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) optionally substitutedby 1 to 3 halogen atoms (e.g., a fluorine atom), or(3) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl);

R^(5b) is

(1) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 3C₁₋₆ alkoxy groups (e.g., methoxy), or(2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy); and

R⁶ is a hydrogen atom; or

R^(5a) and R⁶ in combination optionally form Ring D′ wherein Ring D′ isa dioxole ring (e.g., 1,3-dioxole), and is fused at the ring formingposition;

Y is a methylene group or an oxygen atom; and

W is a C₁₋₂ alkylene group (e.g., methylene, ethylene (—CH₂—CH₂—))

or a salt thereof.

[Compound I-C1]

A compound wherein

Ring A is a benzene ring optionally further substituted by 1 to 3(preferably 1 or 2) halogen atoms (e.g., a fluorine atom);

R¹ is a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))

-   -   wherein    -   Q is a carbon atom or a silicon atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently a C₁₋₆ alkyl        group (e.g., methyl), or    -   R^(1a) is bonded to one substituent for Ring A to form a C₂₋₁₀        cycloalkene ring (e.g., cyclopentene);

R¹¹ is —C(═O)—R⁴;

R¹ is

(1) a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g.,azetidinyl) optionally substituted by 1 to 3 substituents selected froma C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 3carboxy groups, or(2) a C₁₋₆ alkyl group (e.g., propyl) optionally substituted by 1 to 3carboxy groups;

the partial structure represented by the formula:

is CR^(5a)═CR⁶ or CR^(5b)═N; and

R^(5a) and R^(5b) are each independently a C₁₋₆ alkoxy group (e.g.,methoxy); and

R⁶ is a hydrogen atom; or

R^(5a) and R⁶ in combination optionally form Ring D′ wherein Ring D′ isa dioxole ring (e.g., 1,3-dioxole), and is fused at the ring formingposition;

Y is a methylene group; and

W is a methylene group

or a salt thereof.

[Compound I-D1]

5-((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-oxopentanoicacid or a salt thereof.

[Compound I-D2]

(1-(((6R)-6-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-8,9-dihydro[1,3]dioxolo[4,5-f]isoquinolin-7(6H)-yl)carbonyl)azetidin-3-yl)aceticacid or a salt thereof.

[Compound I-D3]

(1-(((5R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)azetidin-3-yl)aceticacid or a salt thereof.

Specific examples of compound (I) include the compounds of Examples 1 to293, which are the compound of formula (I) or a salt thereof or asolvate thereof (e.g., a hydrate (e.g., monohydrate, dihydrate, etc.)).

Among compound (I), examples of compound (Ia) include the followingcompounds.

[Compound Ia-A1]

A compound wherein

Ring A is a 6-membered aromatic ring (e.g., a benzene ring, a pyridinering) optionally further substituted by 1 to 3 (preferably 1 or 2)substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (2) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (3) a cyano group;

R¹ is

(1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))

-   -   wherein    -   Q is a carbon atom or a silicon atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy, ethoxy)        optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine        atom),    -   (b) a C₁₋₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl),    -   (c) a carbamoyl group optionally mono- or di-substituted by        substituent(s) selected from        -   (i) a C₁₋₆ alkyl group (e.g., ethyl), and        -   (ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),    -   (d) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., oxadiazolyl (1,3,4-oxadiazolyl)) optionally substituted        by 1 to 3 C₁₋₆ alkyl groups (e.g., methyl), or    -   (e) a 3- to 8-membered monocyclic non-aromatic        heterocyclylcarbonyl group (e.g., pyrrolidinylcarbonyl), or        R^(1c) is bonded to one substituent for Ring A to form    -   (a) a C₃₋₁₀ cycloalkene ring (e.g., cyclopentene), or    -   (b) a 3- to 14-membered non-aromatic heterocycle (e.g.,        dihydrofuran), or        (2) a neo-pentyl group;

R⁴ is

(1) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,isoxazolyl) optionally substituted by 1 to 3 hydroxy groups,(2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g.,dihydropyridyl (1,2-dihydropyridyl), pyrrolidinyl) optionallysubstituted by 1 to 3 oxo groups,(3) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, butyl, isobutyl,neo-pentyl) optionally substituted by 1 to 5 (preferably 1 to 3)substituents selected from

-   -   (a) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolidinyl, piperidyl, imidazolidinyl,        pyrrolidinyl, oxazolidinyl, tetrahydropyrimidinyl        (1,2,3,4-tetrahydropyrimidinyl), dihydropyrimidinyl        (3,4-dihydropyrimidinyl), dihydropyridyl (1,2-dihydropyridyl),        1,1-dioxidotetrahydrothiopyranyl) optionally substituted by 1 to        5 (preferably 1 to 3) substituents selected from        -   (i) an oxo group, and        -   (ii) a C₁₋₆ alkyl group (e.g., methyl),    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., isoxazolyl, oxadiazolyl (1,3,4-oxadiazolyl), pyridyl,        tetrazolyl (5-tetrazolyl)) optionally substituted by 1 to 3        substituents selected from        -   (i) a hydroxy group,        -   (ii) a C₁₋₆ alkyl group (e.g., methyl), and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),    -   (e) a carboxy group,    -   (f) a 8- to 14-membered fused polycyclic (preferably bi- or        tri-cyclic) aromatic heterocyclic group (e.g., indazolyl        (1H-indazolyl)),    -   (g) a halogen atom (e.g., a fluorine atom),    -   (h) a cyano group, and    -   (i) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 carboxy groups,        (4) an amino group optionally mono- or di-substituted by 5- or        6-membered monocyclic aromatic heterocyclic group(s) (e.g.,        pyridazinyl, pyrazolyl) optionally substituted by 1 to 3 C₁₋₆        alkyl groups (e.g., methyl),        (5) a carboxy group, or        (6) a carbamoyl group;

Ring B is a benzene ring, a pyridine ring or a 1,2-dihydropyridine ring;

the partial structure represented by the formula:

is CR^(5a)═CR⁶, CR^(5b)═N or C(═O)—NR⁷; and

R^(5a) is a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1to 3 C₁₋₆ alkoxy groups (e.g., methoxy, ethoxy), or a C₁₋₆ alkoxy group(e.g., methoxy, ethoxy);

R^(5b) is a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy);

R⁶ is a hydrogen atom; and

R⁷ is a C₁₋₆ alkyl group (e.g., methyl);

Y is a methylene group or an oxygen atom; and

W is a C₁₋₂ alkylene group (e.g., methylene, ethylene)

or a salt thereof.

[Compound Ia-B1]

A compound wherein

Ring A is a benzene ring optionally further substituted by 1 to 3(preferably 1 or 2) substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (2) a cyano group;

R¹ is a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))

-   -   wherein    -   Q is a carbon atom or a silicon atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently    -   (a) a C₁₋₆ alkyl group (e.g., methyl), or    -   (b) a C₁₋₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl), or        R^(1c) is bonded to one substituent for Ring A to form a C₃₋₁₀        cycloalkene ring (e.g., cyclopentene);

R⁴ is

(1) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,isoxazolyl) optionally substituted by 1 to 3 hydroxy groups,(2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g.,dihydropyridyl (1,2-dihydropyridyl), pyrrolidinyl) optionallysubstituted by 1 to 3 oxo groups, or(3) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 5 (preferably 1 to 3) substituents selected from

-   -   (a) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., dihydropyrimidinyl (3,4-dihydropyrimidinyl))        optionally substituted by 1 to 3 oxo groups,    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., isoxazolyl, oxadiazolyl (1,3,4-oxadiazolyl), pyridyl)        optionally substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group,        -   (ii) a C₁₋₆ alkyl group (e.g., methyl), and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (c) a hydroxy group;

Ring B is a benzene ring or a pyridine ring;

the partial structure represented by the formula:

is CR^(5a)═CR⁶ or CR^(5b)═N; and

R^(5a) is a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1to 3 C₁₋₆ alkoxy groups (e.g., methoxy), or a C₁₋₆ alkoxy group (e.g.,methoxy, ethoxy);

R^(5b) is a C₁₋₆ alkoxy group (e.g., methoxy); and

R⁶ is a hydrogen atom;

Y is a methylene group or an oxygen atom; and

W is a C₁₋₂ alkylene group (e.g., methylene, ethylene)

or a salt thereof.

Examples of salts of compound (I) and (Ia) include metal salts, ammoniumsalts, salts with organic base, salts with inorganic acid, salts withorganic acid, salts with basic or acidic amino acids, and the like.Preferable examples of the metal salt include alkaline metal salts suchas sodium salt, potassium salt and the like; alkaline earth metal saltssuch as calcium salt, magnesium salt, barium salt and the like; aluminumsalts, and the like. Preferable examples of the salt with organic baseinclude salts with trimethylamine, triethylamine, pyridine, picoline,2,6-lutidine, ethanolamine, diethanolamine, triethanolamine,cyclohexylamine, dicyclohexylamine, N,N′-dibenzylethylenediamine and thelike. Preferable examples of the salt with inorganic acid include saltswith hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like. Preferable examples of the salt withorganic acid include salts with formic acid, acetic acid,trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid andthe like. Preferable examples of the salt with basic amino acid includesalts with arginine, lysine, ornithine and the like. Preferable examplesof the salt with acidic amino acid include salt with aspartic acid,glutamic acid and the like.

Among them, pharmaceutically acceptable salts are preferable. Forexample, if the compound has an acidic functional group therein,examples of the salt include inorganic salts such as alkaline metalsalts (e.g., sodium salt, potassium salt and the like), alkaline earthmetal salts (e.g., calcium salt, magnesium salt, barium salt and thelike) and the like; ammonium salt, and the like. If the compound has abasic functional group therein, examples of the salt thereof includesalts with inorganic acids such as hydrochloric acid, hydrobromic acid,nitric acid, sulfuric acid, phosphoric acid and the like, and salts withorganic acids such as acetic acid, phthalic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid,methanesulfonic acid, p-toluenesulfonic acid and the like.

The production method of the compound (I) or (Ia) of the presentinvention is explained below.

The intermediates produced in the following production methods may beisolated and purified according to methods such as columnchromatography, recrystallization, distillation and the like, or may bedirectly used without isolation for the next step.

Ring A represented by the formula:

in the following production methods is used for the same meaning as RingA represented by the formula:

which is defined in compounds (I) and (Ia) of the present invention.

Compound (Ia) or a salt thereof of the present invention can be producedaccording to the following Method A.

[Method A]

wherein each symbol is as defined above.

(Step 1)

This step is a step of subjecting compound (II) or a salt thereof to anacylation reaction to convert compound (II) or a salt thereof tocompound (Ia) or a salt thereof.

In the acylation reaction, compound (Ia) or a salt thereof can beproduced by reacting compound (II) or a salt thereof with a compoundrepresented by the formula:

wherein the symbol is as defined above (hereinafter to be referred to ascompound (IV)) or a salt thereof.

Compound (IV) or a salt thereof may be a commercially available product,or can also be produced according to a method known per se or a methodanalogous thereto.

The acylation reaction can be carried out according to a method knownper se, for example, the method described in Jikken Kagaku Kouza, 4thEdition, 1991, vol. 22, organic synthesis IV (the Chemical Society ofJapan ed.) and the like, or a method analogous thereto. Examples of themethod include a method using a condensing agent, a method via areactive derivative, and the like.

Examples of the condensing agent to be used for the “method using acondensing agent” include(dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaneiminiumhexafluorophosphorate (HATU),1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethylamino-morpholino)]carbeniumhexafluorophosphorate (COMU),2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P),dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC),N-ethyl-N′-3-dimethylaminopropylcarbodiimide and a hydrochloride thereof(WSC, WSC.HCl, EDCI), benzotriazol-1-yl-tris(dimethylamino)phosphoniumhexafluorophosphorate (BOP), diphenylphosphorylazide (DPPA) and thelike. They can be used alone or in combination with an additive (e.g.,N-hydroxysuccinimide, 1-hydroxybenzotriazole or3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine, etc.). The amount ofthe condensing agent to be used is about 1 to 10 mol equivalent,preferably about 1 to 2 mol equivalent, per 1 mol of compound (II). Theamount of the additive to be used is about 1 to 10 mol equivalent,preferably about 1 to 2 mol equivalent, per 1 mol of compound (II).

The above-mentioned reaction is generally carried out in a solvent thatdoes not adversely influence the reaction, and a base may be added forthe progress of the reaction. Examples of the solvent includehydrocarbons (benzene, toluene, etc.), ethers (diethyl ether,1,4-dioxane, tetrahydrofuran, etc.), esters (ethyl acetate, etc.),halogenated hydrocarbons (chloroform, dichloromethane, etc.), amides(N,N-dimethylformamide, etc.), aromatic amines (pyridine, etc.), waterand the like, and they may be mixed as appropriate. Examples of the baseinclude alkali metal hydroxides (sodium hydroxide, potassium hydroxide,etc.), hydrogen carbonates (sodium hydrogen carbonate, potassiumhydrogen carbonate, etc.), carbonates (sodium carbonate, potassiumcarbonate, etc.), acetates (sodium acetate, etc.), tertiary amines(trimethylamine, triethylamine, N-methylmorpholine, diisopropylamine,etc.), aromatic amines (pyridine, picoline, N,N-dimethylaniline,4-dimethylaminopyridine, etc.) and the like. The amount of the base tobe used is generally about 1 to 100 mol equivalent, preferably about 1to 5 mol equivalent, per 1 mol of compound (II). The reactiontemperature is generally about −80 to 150° C., preferably about 0 to 50°C., and the reaction time is generally about 0.5 to 48 hr, preferably0.5 to 16 hr.

Examples of the reactive derivative in the “method via a reactivederivative” include a compound represented by the formula:

wherein LG is a leaving group, and the other symbols are as definedabove (hereinafter to be referred to as compound (IVa)) or a saltthereof (e.g., acid halides, anhydrides, mixed anhydrides, activatedesters, etc.) or chemical equivalents thereof (isocyanates,thioisocyanates, etc.) and the like.

Examples of the leaving group for LG include halogen atoms (a chlorineatom, a bromine atom, an iodine atom, etc.), substituted sulfonyloxygroups (C₁₋₆ alkylsulfonyloxy groups such as methanesulfonyloxy,ethanesulfonyloxy and the like; C₆₋₁₄ arylsulfonyloxy groups such asbenzenesulfonyloxy, p-toluenesulfonyloxy and the like; C₇₋₁₆aralkylsulfonyloxy groups such as benzylsulfonyloxy group and the like,etc.), acyloxy groups (acetoxy, benzoyloxy, etc.), an oxy groupsubstituted by a heterocyclic group or an aryl group(2,5-dioxo-1-pyrrolidinyl, benzotriazolyl, quinolyl, 4-nitrophenyl,etc.), heterocyclic groups (imidazolyl, etc.) and the like. LG isoptionally bonded to R⁴ to form a ring, and compound (IVa) may be, forexample, anhydrides (dihydro-2H-pyran-2,6(3H)-dione, oxepane-2,7-dione,4-methyldihydro-2H-pyran-2,6(3H)-dione,4,4-dimethyldihydro-2H-pyran-2,6(3H)-dione,4-methylmorpholine-2,6-dione,4-hydroxy-4-methyldihydro-2H-pyran-2,6(3H)-dione, succinic anhydride,etc.).

The conversion of compound (IV) to the reactive derivative (compound(IVa)) can be carried out according to a method known per se. Forexample, The conversion to the acid halide can be carried out byemploying a method using an acid halide (e.g., thionyl chloride, oxalylchloride, etc.), a method using a halide of phosphorus and phosphoricacid (e.g., phosphorus trichloride, phosphorus pentachloride, etc.), andthe like. The method using a reactive derivative is generally carriedout in a solvent that does not adversely influence the reaction, whichvaries depending on the kind of compound (IVa), and a base may be addedfor the progress of the reaction. The kind and amount of the solvent andbase to be used for the reaction, the reaction temperature and thereaction time are the same as in the above-mentioned “method using acondensing agent”.

(Step 2)

This step is a step of subjecting compound (II) or a salt thereof to anureation reaction to convert compound (II) or a salt thereof to compound(Ia) or a salt thereof.

In the ureation reaction, compound (Ia) or a salt thereof can beproduced by reacting a compound represented by the formula:

R⁴—H  (V)

wherein the symbol is as defined above (hereinafter to be referred to ascompound (V)) or a salt thereof with a carbonylating agent, and thenreacting the resulting reactive intermediate with compound (II) or asalt thereof, or by reacting compound (II) or a salt thereof with acarbonylating agent, and then reacting the resulting reactiveintermediate with compound (V) or a salt thereof.

Compound (V) may be a commercially available product, or can also beproduced according to a method known per se or a method analogousthereto.

Examples of the carbonylating agent to be used in this step includetriphosgene, chloroformic acid 4-nitrophenyl or carbonyldiimidazole andthe like. The amount of the carbonylating agent to be used is about 1 to10 mol equivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (II).

The above-mentioned reaction is generally carried out in a solvent thatdoes not adversely influence the reaction, and a base may be added forthe progress of the reaction. Examples of the solvent includehydrocarbons (benzene, toluene, etc.), ethers (diethyl ether,1,4-dioxane, tetrahydrofuran, etc.), esters (ethyl acetate, etc.),halogenated hydrocarbons (chloroform, dichloromethane, etc.), amides(N,N-dimethylformamide, etc.) and the like, and they may be mixed asappropriate. Examples of the base include alkali metal hydroxides(sodium hydroxide, potassium hydroxide, etc.), hydrogen carbonates(sodium hydrogen carbonate, potassium hydrogen carbonate, etc.),carbonates (sodium carbonate, potassium carbonate, etc.), acetates(sodium acetate, etc.), tertiary amines (trimethylamine, triethylamine,N-methylmorpholine, etc.), aromatic amines (pyridine, picoline,N,N-dimethylaniline, etc.) and the like. The amount of the base to beused is generally about 1 to 100 mol equivalent, preferably about 1 to 5mol equivalent, per 1 mol of compound (II). The reaction temperature isgenerally about −80 to 150° C., preferably about 0 to 50° C., and thereaction time is generally about 0.5 to 100 hr, preferably 0.5 to 60 hr.

The reactive intermediate obtained by the reaction of compound (V) or asalt thereof with a carbonylating agent may be reacted with compound(II) or a salt thereof after isolation.

The reactive intermediate obtained by the reaction of compound (II) or asalt thereof with a carbonylating agent may be reacted with compound (V)or a salt thereof after isolation.

(Step 3)

This step is a step of reacting compound (III) or a salt thereof with acompound represented by the formula:

wherein each symbol is as defined above (hereinafter to be referred toas compound (VI)) or a salt thereof in the presence of a condensingagent to produce compound (Ia) or a salt thereof.

Compound (VI) or a salt thereof may be a commercially available product,or can also be produced according to a method known per se or a methodanalogous thereto, or the below-mentioned method.

This step can be performed in the same manner as in the method describedin Step 1 of Method A.

The raw material used in Method A can be produced according to thefollowing Methods B-D.

[Method B]

wherein R⁸ is a hydrocarbon group optionally having substituent(s), PGis an amino-protecting group, and the other symbols are as definedabove.

Examples of the amino-protecting group for PG include atert-butoxycarbonyl (Boc) group, a benzyl (Bn) group, a 4-methoxybenzyl(PMB) group, a trifluoroacetyl (CF₃CO) group and the like.

Compound (II) or a salt thereof of the present invention can be producedaccording to the following Step 1 to Step 5.

(Step 1)

This step is a step of subjecting compound (VII) or a salt thereof andcompound (VIII) or a salt thereof to a cyclization reaction using anacid to produce compound (IX) or a salt thereof.

Examples of the acid to be used for this reaction include mineral acids(hydrochloric acid, hydrobromic acid, sulfuric acid, etc.), Lewis acids(aluminium chloride, tin chloride, zinc bromide, etc.) and the like.Among them, hydrochloric acid, hydrobromic acid and aluminium chlorideare preferable. While the amount of the acid to be used varies dependingon the kind of the solvent and the other reaction condition, it isgenerally about 1 mol equivalent or more per 1 mol of compound (VII).

Compound (VII) or a salt thereof and compound (VIII) or a salt thereofto be used for this reaction may be a commercially available product, orcan also be produced according to a method known per se or a methodanalogous thereto.

The amount of compound (VIII) to be used is generally about 1 to 10 molequivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (VII).

This step is performed in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include alcohols (methanol, ethanol, propanol, 2-propanol,butanol, isobutanol, tert-butanol, etc.), aromatic hydrocarbons(benzene, toluene, xylene, etc.), aliphatic hydrocarbons (hexane,heptane, etc.), halogenated hydrocarbons (dichloromethane, chloroform,etc.), ethers (diethyl ether, diisopropyl ether, tert-butyl methylether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.),nitriles (acetonitrile, etc.), esters (ethyl acetate, etc.) and thelike.

The reaction temperature is, for example, within about 0 to 200° C.,preferably about 25 to 100° C. While the reaction time varies dependingon the kind of compound (VII) or a salt thereof, the reactiontemperature and the like, it is, for example, about 0.5 to 100 hr,preferably about 0.5 to 24 hr.

(Step 2)

This step is a step of subjecting compound (IX) or a salt thereof to anamino-protecting reaction to produce compound (X) or a salt thereof.

When the amino group is protected by a Boc group, the reaction iscarried out by reacting compound (IX) or a salt thereof withdi-tert-butyl dicarbonate (Boc₂O) in the presence of a base, in asolvent that does not adversely influence the reaction.

Examples of the base to be used in this step include inorganic bases(alkali metal hydrides such as sodium hydride, lithium hydride and thelike, alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide, potassium hydroxide and the like, alkali metal hydrogencarbonates such as sodium hydrogen carbonate, potassium hydrogencarbonate and the like, alkali metal carbonates such as lithiumcarbonate, sodium carbonate, potassium carbonate, cesium carbonate andthe like, alkali metal alkoxides such as sodium methoxide, sodiumethoxide and the like, etc.), organic bases (amines such astrimethylamine, triethylamine, diisopropylethylamine and the like,cyclic amines such as pyridine, 4-dimethylaminopyridine and the like,etc.) and the like. Among them, sodium hydride and triethylamine arepreferable. While the amount of the base to be used varies depending onthe kind of the solvent and the other reaction condition, it isgenerally about 1 to 10 mol equivalent, preferably about 1 to 5 molequivalent, per 1 mol of compound (IX).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons (benzene, toluene, xylene, etc.),aliphatic hydrocarbons (hexane, heptane, etc.), halogenated hydrocarbons(dichloromethane, chloroform, etc.), ethers (diethyl ether, diisopropylether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, etc.), nitriles (acetonitrile, etc.), esters (ethylacetate, etc.), amides (N,N-dimethylformamide, etc.), sulfoxides(dimethyl sulfoxide, etc.), and water and the like. These solvent may beused in a mixture of two or more kinds thereof in an appropriate ratio.

The amount of the Boc₂O to be used in this step is about 1 to 10 molequivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (IX).

The reaction temperature is, for example, within about −10 to 100° C.While the reaction time varies depending on the kind of compound (IX) ora salt thereof, the reaction temperature and the like, it is, forexample, about 0.5 to 100 hr, preferably about 0.5 to 24 hr.

When the amino group is protected by a Bn group, the reaction is carriedout by reacting compound (IX) or a salt thereof with benzaldehyde in asolvent that does not adversely influence the reaction, and thentreating the resulting compound with a reducing agent, or by reactingcompound (IX) or a salt thereof with benzyl bromide in the presence of abase, in a solvent that does not adversely influence the reaction.

When compound (IX) or a salt thereof is reacted with benzaldehyde,examples of the solvent that does not adversely influence the reactioninclude hydrocarbons (heptane, hexane, toluene, xylene, etc.),halogenated hydrocarbons (chloroform, dichloromethane,1,2-dichloroethane, etc.), ethers (diethyl ether, tetrahydrofuran,1,4-dioxane, etc.), esters (ethyl acetate, tert-butyl acetate, etc.),alcohols (methanol, ethanol, 2-propanol, etc.), nitriles (acetonitrile,butyronitrile, etc.), amides (N,N-dimethylformamide,N,N-dimethylacetamide, etc.), sulfoxides (dimethyl sulfoxide, etc.), andmixed solvents thereof.

Examples of the reducing agent to be used for this reaction includemetal hydrides (e.g., sodium borohydride, lithium borohydride, zincborohydride, sodium cyanoborohydride, sodium triacetoxyborohydride,lithium cyanoborohydride, diisobutylaluminium hydride, aluminiumhydride, lithium aluminium hydride, borane complex (borane-THF complex,catecholborane, etc.) and the like. The amount of the metal hydride tobe used is about 1 to about 50 mol per 1 mol of compound (IX).

In this reaction, a catalyst may be added for the progress of thereaction, if necessary. Examples of the catalyst include mineral acids(hydrochloric acid, hydrobromic acid, sulfuric acid, etc.), carboxylicacids (formic acid, acetic acid, propionic acid, trifluoroacetic acid,etc.), sulfonic acids (methanesulfonic acid, p-toluenesulfonic acid,etc.), Lewis acids (aluminium chloride, zinc chloride, zinc bromide,boron trifluoride, titanium chloride, etc.), acetates (sodium acetate,potassium acetate, etc.), molecular sieves (molecular sieves 3A, 4A, 5A,etc.), dehydrating agents (magnesium sulfate, etc.) and the like. Theamount of the catalyst to be used is generally about 0.01 to 50 molequivalent, preferably about 0.1 to 10 mol equivalent, per 1 mol ofcompound (IX).

The amount of the benzaldehyde to be used is generally about 1 to 10 molequivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (IX).

The reaction temperature is generally about 0° C.−200° C., preferablyabout 20° C. to 150° C., and the reaction time is generally about 0.5 hrto 48 hr, preferably about 0.5 hr to 24 hr.

When compound (IX) or a salt thereof is reacted with benzyl bromide,examples of the base to be used for this reaction include inorganicbases (alkali metal hydrides such as sodium hydride, lithium hydride andthe like, alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide, potassium hydroxide and the like, alkali metal hydrogencarbonates such as sodium hydrogen carbonate, potassium hydrogencarbonate and the like, alkali metal carbonates such as lithiumcarbonate, sodium carbonate, potassium carbonate, cesium carbonate andthe like, alkali metal alkoxides such as sodium methoxide, sodiumethoxide and the like, etc.), organic bases (amines such astrimethylamine, triethylamine, diisopropylethylamine and the like,cyclic amines such as pyridine, 4-dimethylaminopyridine and the like,etc.) and the like. Among them, potassium carbonate is preferable. Whilethe amount of the base to be used varies depending on the kind of thesolvent and the other reaction condition, it is generally about 1 to 10mol equivalent, preferably about 1 to 5 mol equivalent, per 1 mol ofcompound (IX).

The amount of the benzyl bromide to be used is generally about 1 to 10mol equivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (IX).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons (benzene, toluene, xylene, etc.),aliphatic hydrocarbons (hexane, heptane, etc.), halogenated hydrocarbons(dichloromethane, chloroform, etc.), ethers (diethyl ether, diisopropylether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, etc.), nitriles (acetonitrile, etc.), esters (ethylacetate, etc.), amides (N,N-dimethylformamide, etc.), sulfoxides(dimethyl sulfoxide, etc.) and the like. Among them, acetonitrile ispreferable. These solvent may be used in a mixture of two or more kindsthereof in an appropriate ratio.

The reaction temperature is, for example, within about 0 to 200° C.,preferably about 25 to 100° C. While the reaction time varies dependingon the kind of compound (IX), the reaction temperature and the like, itis, for example, about 0.5 to 100 hr, preferably about 0.5 to 24 hr.

When the amino group is protected by a PMB group, the reaction iscarried out by reacting compound (IX) or a salt thereof with4-methoxybenzaldehyde in a solvent that does not adversely influence thereaction, and then treating the resulting compound with a reducingagent.

The kind and amount of the solvent, reducing agent, reagent and additiveto be used in this step, the reaction temperature and the reaction timeare the same as in the reaction of the amino group with a Bn group.

When the amino group is protected by a CF₃CO group, the reaction iscarried out by reacting compound (IX) or a salt thereof withtrifluoroacetic anhydride in the presence of a base, in a solvent thatdoes not adversely influence the reaction. The kind and amount of thesolvent, reducing agent, reagent and additive to be used in this step,the reaction temperature and the reaction time are the same as in thereaction of the amino group with a Bn group.

(Step 3)

This step is a step of subjecting compound (X) or a salt thereof tohydrolysis to convert compound (X) or a salt thereof to compound (XI) ora salt thereof. This reaction can be carried out according to a methodknown per se, generally in the presence of an acid or a base, in asolvent that does not adversely influence the reaction, if necessary.

Examples of the acid include mineral acids (hydrochloric acid,hydrobromic acid, sulfuric acid, etc.), carboxylic acids (acetic acid,trifluoroacetic acid, trichloroacetic acid, etc.), sulfonic acids(methanesulfonic acid, p-toluenesulfonic acid, etc.), Lewis acids(aluminium chloride, tin chloride, zinc bromide, etc.) and the like.Where necessary, they may be used in a mixture of two or more kindsthereof. While the amount of the acid to be used varies depending on thekind of the solvent and the other reaction condition, it is generallyabout 0.1 mol equivalent or more per 1 mol of compound (X), The acid maybe used as a solvent.

Examples of the base include inorganic bases (alkali metal hydroxidessuch as lithium hydroxide, sodium hydroxide, potassium hydroxide and thelike, alkali metal hydrogen carbonates such as sodium hydrogencarbonate, potassium hydrogen carbonate and the like, alkali metalcarbonates such as sodium carbonate, potassium carbonate and the like,alkoxides such as sodium methoxide, sodium ethoxide and the like, etc.),organic bases (amines such as trimethylamine, triethylamine,diisopropylethylamine and the like, cyclic amines such as pyridine,4-dimethylaminopyridine and the like, etc.) and the like. Among them,sodium hydroxide is preferable. While the amount of the base to be usedvaries depending on the kind of the solvent and the other reactioncondition, it is generally about 0.1 to 10 mol equivalent, preferablyabout 1 to 5 mol equivalent, per 1 mol of compound (X).

Examples of the solvent that does not adversely influence the reactioninclude alcohols (methanol, ethanol, propanol, 2-propanol, butanol,isobutanol, tert-butanol, etc.), hydrocarbons (benzene, toluene, xylene,hexane, heptane, etc.), halogenated hydrocarbons (dichloromethane,chloroform, etc.), ethers (diethyl ether, diisopropyl ether, tert-butylmethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.),nitriles (acetonitrile, etc.), carboxylic acids (acetic acid, etc.),amides (N,N-dimethylformamide, N,N-dimethylacetamide, etc.), sulfoxides(dimethyl sulfoxide, etc.), water and the like. Among them, ethanol,tetrahydrofuran and water are preferable. These solvent may be used in amixture of two or more kinds thereof in an appropriate ratio.

The reaction temperature is, for example, within about −50 to 200° C.,preferably about 0 to 100° C. While the reaction time varies dependingon the kind of compound (X) or a salt thereof, the reaction temperatureand the like, it is, for example, about 0.5 to 100 hr, preferably about0.5 to 24 hr.

(Step 4)

This step is a step of reacting compound (XI) or a salt thereof withcompound (VI) or a salt thereof in the presence of a condensing agent toproduce compound (XII) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method A or Step 1 of Method A.

(Step 5)

This step is a step of subjecting compound (XII) or a salt thereof to adeprotection reaction to produce compound (II) or a salt thereof.

The deprotection reaction can be carried out according to a method knownper se (e.g., the method described in “Protective Groups in OrganicSynthesis, 3rd Ed”, Wiley-Interscience, Inc. (1999) (Theodora W. Greene,Peter G. M. Wuts)).

When PG is a Boc group, the deprotection reaction can be carried out inthe presence of an acid, in a solvent that does not adversely influencethe reaction.

Examples of the acid include mineral acids (hydrochloric acid,hydrobromic acid, sulfuric acid, etc.), carboxylic acids (acetic acid,trifluoroacetic acid, trichloroacetic acid, etc.), sulfonic acids(methanesulfonic acid, p-toluenesulfonic acid, etc.), Lewis acids(aluminium chloride, tin chloride, zinc bromide, etc.) and the like.Where necessary, they may be used in a mixture of two or more kindsthereof. While the amount of the acid to be used varies depending on thekind of the solvent and the other reaction condition, it is generallyabout 0.1 mol equivalent or more per 1 mol of compound (XII). The acidmay be used as a solvent.

Examples of the solvent that does not adversely influence the reactioninclude alcohols (methanol, ethanol, propanol, 2-propanol, butanol,isobutanol, tert-butanol, etc.), aromatic hydrocarbons (benzene,toluene, xylene, etc.), aliphatic hydrocarbons (hexane, heptane, etc.),halogenated hydrocarbons (dichloromethane, chloroform, etc.), ethers(diethyl ether, diisopropyl ether, tert-butyl methyl ether,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), nitriles(acetonitrile, etc.), esters (ethyl acetate, etc.), carboxylic acids(acetic acid, etc.), amides (N,N-dimethylformamide, etc.), sulfoxides(dimethyl sulfoxide, etc.), water and mixed solvents thereof.

The reaction temperature is, for example, within about −50 to 200° C.,preferably about 0 to 100° C. While the reaction time varies dependingon the kind of compound (XII), the reaction temperature and the like, itis, for example, about 0.5 to 100 hr, preferably about 0.5 to 24 hr.

When PG is a Bn group or a PMB group, the deprotection reaction can becarried out by a catalytic hydrogenation reaction, an oxidation reactionor an acid hydrolysis.

The catalytic hydrogenation reaction can be carried out in the presenceof a catalyst under hydrogen atmosphere. Examples of the catalystinclude palladiums such as palladium on carbon, palladium hydroxide oncarbon, palladium oxide and the like; nickels such as Raney-nickelcatalyst and the like; platinums such as platinum oxide, platinum oncarbon and the like; rhodiums such as rhodium on carbon and the like,and the like. The amount thereof to be used is generally about 0.001 to1 mol, preferably about 0.01 to 0.5 mol, per 1 mol of compound (XII).

The catalytic hydrogenation reaction is generally carried out in asolvent inert to the reaction. Examples of the solvent include alcoholssuch as methanol, ethanol, propanol, butanol and the like; hydrocarbonssuch as benzene, toluene, xylene and the like; halogenated hydrocarbonssuch as dichloromethane, chloroform and the like; ethers such as diethylether, 1,4-dioxane, tetrahydrofuran and the like; esters such as ethylacetate and the like; amides such as N,N-dimethylformamide and the like;carboxylic acids such as acetic acid and the like; water and mixturesthereof.

The hydrogen pressure for the reaction is generally about 1 to 50 atm,preferably about 1 to 10 atm. The reaction temperature is generallyabout 0° C. to 150° C., preferably about 20° C. to 100° C., and thereaction time is generally about 5 min to 72 hr, preferably about 0.5 hrto 40 hr.

Examples of the oxidizing agent to be used for the oxidation reactioninclude ammonium cerium(IV) nitrate. The amount thereof to be used isabout 1 to about 50 mol per 1 mol of compound (XII).

The oxidation reaction is carried out in a solvent that does notadversely influence the reaction. Examples of the solvent includenitriles (e.g., acetonitrile), hydrocarbons (e.g., benzene, toluene,xylene), halogenated hydrocarbons (e.g., dichloromethane, chloroform),ethers (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran), amides(e.g., N,N-dimethylformamide), water and mixtures thereof.

The reaction temperature is generally about 0° C. to 150° C., preferablyabout 20° C. to 100° C., and the reaction time is generally about 5 minto 72 hr, preferably about 0.5 hr to 40 hr.

Examples of the acid to be used for the acid hydrolysis includetrifluoroacetic acid. The acid may be used as a solvent. The reactiontemperature is generally about 0° C. to 150° C., preferably about 0° C.to 30° C., and the reaction time is generally about 5 min to 72 hr,preferably about 0.5 hr to 40 hr.

When PG is a CF₃CO group, the deprotection reaction can be carried outin the presence of a base, in a solvent that does not adverselyinfluence the reaction.

Examples of the base include inorganic bases (alkali metal hydroxidessuch as lithium hydroxide, sodium hydroxide, potassium hydroxide and thelike, alkali metal hydrogen carbonates such as sodium hydrogencarbonate, potassium hydrogen carbonate and the like, alkali metalcarbonates such as sodium carbonate, potassium carbonate and the like,alkoxides such as sodium methoxide, sodium ethoxide and the like, etc.)and the like. The amount of the base to be used is about 1 to 100 molequivalent, preferably about 1 to 20 mol equivalent, per 1 mol ofcompound (XII).

Examples of the solvent that does not adversely influence the reactioninclude hydrocarbons (benzene, toluene, xylene, hexane, heptane, etc.),halogenated hydrocarbons (dichloromethane, chloroform, etc.), ethers(diethyl ether, diisopropyl ether, tert-butyl methyl ether,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), nitriles(acetonitrile, etc.), amides (N,N-dimethylformamide,N,N-dimethylacetamide, etc.), sulfoxides (dimethyl sulfoxide, etc.),water and the like. These solvent may be used in a mixture of two ormore kinds thereof in an appropriate ratio.

The reaction temperature is, for example, within about −50 to 200° C.,preferably about 0 to 100° C. While the reaction time varies dependingon the kind of compound (XII), the reaction temperature and the like, itis, for example, about 0.5 to 24 hr, preferably about 0.5 to 2 hr.

Compound (III) or a salt thereof of the present invention can beproduced according to the following Step 6 and Step 7.

(Step 6)

This step is a step of subjecting compound (IX) or a salt thereof to anacylation reaction with compound (IV) or a salt thereof to convertcompound (IX) or a salt thereof to compound (XIII) or a salt thereof, ora step of subjecting compound (IX) or a salt thereof to an ureationreaction with compound (V) or a salt thereof to convert compound (IX) ora salt thereof to compound (XIII) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 1 or Step 2 of Method A.

(Step 7)

This step is a step of subjecting compound (XIII) or a salt thereof tohydrolysis to convert compound (XIII) or a salt thereof to compound(III) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method B.

A compound wherein

is CR^(5a)═CR⁶, R^(5a) is a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy),and R⁶ is a hydrogen atom in formula (Ia), which is a raw materialcompound in Method A, can be produced according to Method C.

[Method C]

wherein R⁹ is an optionally substituted C₁₋₆ alkyl group, and the othersymbols are as defined above.

(Step 1)

This step is a step of subjecting compound (XIV) or a salt thereof andcompound (VIIIa) to a cyclization reaction using an acid to producecompound (XV) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 1 of Method B.

(Step 2)

This step is a step of subjecting compound (XV) or a salt thereof to anamino-protecting reaction to produce compound (XVI) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 2 of Method B.

(Step 3)

This step is a step of subjecting compound (XVI) or a salt thereof to analkylation reaction with a compound represented by the formula:

R⁹-LG  (XXXV)

wherein each symbol is as defined above (hereinafter to be referred toas compound (XXXV)) or a salt thereof in the presence of a base toproduce compound (XVII) or a salt thereof.

Compound (XXXV) may be a commercially available product, or can also beproduced according to a method known per se or a method analogousthereto.

Examples of the base to be used for this reaction include inorganicbases (alkali metal hydrides such as sodium hydride, lithium hydride andthe like, alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide, potassium hydroxide and the like, alkali metal hydrogencarbonates such as sodium hydrogen carbonate, potassium hydrogencarbonate and the like, alkali metal carbonates such as lithiumcarbonate, sodium carbonate, potassium carbonate, cesium carbonate andthe like, and the like. While the amount of the base to be used variesdepending on the kind of the solvent and the other reaction condition,it is generally about 1 to 10 mol equivalent, preferably about 1 to 5mol equivalent, per 1 mol of compound (XVI).

The amount of compound (XXXV) to be used is generally about 1 to 10 molequivalent, preferably about 1 to 3 mol equivalent, per 1 mol ofcompound (XVI).

This step is performed in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include aromatic hydrocarbons (benzene, toluene, xylene,etc.), aliphatic hydrocarbons (hexane, heptane, etc.), halogenatedhydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether,diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, etc.), nitriles (acetonitrile, etc.),esters (ethyl acetate, etc.), amides (N,N-dimethylformamide, etc.),sulfoxides (dimethyl sulfoxide, etc.) and the like. These solvent may beused in a mixture of two or more kinds thereof in an appropriate ratio.

The reaction temperature is, for example, within about −75 to 200° C.,preferably about −10 to 30° C. While the reaction time varies dependingon the kind of compound (XVI) or a salt thereof, the reactiontemperature and the like, it is, for example, about 0.5 to 100 hr,preferably about 0.5 to 24 hr.

When R⁹O of compound (XVII) is F₂HCO, sodium2-chloro-2,2-difluoroacetate can be preferably used as compound (XXXV).

(Step 4)

This step is a step of subjecting compound (XVII) or a salt thereof tohydrolysis to convert compound (XVII) or a salt thereof to compound(XVIII) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method B.

(Step 5)

This step is a step of reacting compound (XVIII) or a salt thereof withcompound (VI) or a salt thereof in the presence of a condensing agent toproduce compound (XIX) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method A or Step 1 of Method A.

(Step 6)

This step is a step of subjecting compound (XIX) or a salt thereof to adeprotection reaction to produce compound (XX) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 5 of Method B.

A compound wherein

is CR^(5b)═N, and R^(5b) is a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy)in formula (Ia), which is a raw material compound in Method A, can beproduced according to Method D.

[Method D]

wherein each symbol is as defined above.

(Step 1)

This step is a step of subjecting compound (XXI) or a salt thereof to ahydroxymethylation reaction to convert compound (XXI) or a salt thereofto compound (XXII) or a salt thereof.

In this reaction, compound (XXII) or a salt thereof can be produced byreacting compound (XXI) or a salt thereof with paraformaldehyde in thepresence of a base.

Examples of the base to be used for this reaction include organiclithium reagents (e.g., n-butyllithium, phenyllithium, lithiumdiisopropylamide), alkali metal hydrides (e.g., sodium hydride, lithiumhydride) and the like. While the amount of the base to be used variesdepending on the kind of the solvent and the other reaction condition,it is generally about 1 to 10 mol equivalent, preferably about 1 to 2mol equivalent, per 1 mol of compound (XXI).

The amount of the paraformaldehyde to be used for this reaction is about1 to 10 mol equivalent, preferably about 1 to 5 mol equivalent, per 1mol of compound (XXI).

This step is performed in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include aromatic hydrocarbons (benzene, toluene, xylene,etc.), aliphatic hydrocarbons (hexane, heptane, etc.), halogenatedhydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether,diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, etc.) and the like. These solvent maybe used in a mixture of two or more kinds thereof in an appropriateratio.

The reaction temperature is, for example, within about −100 to 50° C.,preferably about −78 to 25° C., and the reaction time is, for example,about 0.5 to 100 hr, preferably about 0.5 to 24 hr.

(Step 2)

This step is a step of subjecting compound (XXII) or a salt thereof to aphthalimidation reaction to convert compound (XXII) or a salt thereof tocompound (XXIII) or a salt thereof.

In this reaction, compound (XXIII) or a salt thereof can be produced byreacting compound (XXII) or a salt thereof with phthalimide in thepresence of an azodicarboxylate reagent and triphenylphosphine.

Examples of the azodicarboxylate reagent to be used for this reactioninclude diethyl azodicarboxylate (DEAD) and diisopropyl azodicarboxylate(DIAD). While the amount of the azodicarboxylate reagent to be usedvaries depending on the kind of the solvent and the other reactioncondition, it is generally about 1 to 5 mol equivalent, preferably about1 to 2 mol equivalent, per 1 mol of compound (XXII).

The amount of the triphenylphosphine to be used for this reaction isabout 1 to 5 mol equivalent, preferably about 1 to 2 mol equivalent, per1 mol of compound (XXII).

The amount of the phthalimide to be used for this reaction is about 1 to5 mol equivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (XXII).

This step is performed in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include aromatic hydrocarbons (benzene, toluene, xylene,etc.), aliphatic hydrocarbons (hexane, heptane, etc.), halogenatedhydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether,diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, etc.) and the like. These solvent maybe used in a mixture of two or more kinds thereof in an appropriateratio.

The reaction temperature is, for example, within about −50 to 50° C.,preferably about 0 to 25° C., and the reaction time is, for example,about 0.5 to 100 hr, preferably about 0.5 to 24 hr.

(Step 3)

This step is a step of reacting compound (XXIII) or a salt thereof withhydrazine to convert to compound (XXIII) or a salt thereof to compound(XXIV) or a salt thereof.

The amount of the hydrazine to be used for this reaction is about 1 to20 mol equivalent, preferably about 3 to 7 mol equivalent, per 1 mol ofcompound (XXIII).

This step is performed in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include alcohols (methanol, ethanol, propanol, 2-propanol,butanol, isobutanol, tert-butanol, etc.), water, nitriles (acetonitrile,etc.), amides (N,N-dimethylformamide, N,N-dimethylacetamide, etc.),sulfoxides (dimethyl sulfoxide, etc.), ethers (diethyl ether,diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, etc.) and the like. These solvent maybe used in a mixture of two or more kinds thereof in an appropriateratio.

The reaction temperature is, for example, within about 0 to 200° C.,preferably about 0 to 100° C., and the reaction time is, for example,about 0.5 to 100 hr, preferably about 0.5 to 24 hr.

(Step 4)

This step is a step of subjecting compound (XXIV) or a salt thereof andcompound (VIIIa) to a cyclization reaction using an acid to producecompound (XXV) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 1 of Method B.

(Step 5)

This step is a step of subjecting compound (XXV) or a salt thereof to anamino-protecting reaction with a tert-butoxycarbonyl (Boc) group toproduce compound (XXVI) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 2 of Method B.

(Step 6)

This step is a step of subjecting compound (XXVI) or a salt thereof toan O-alkylation reaction to produce compound (XXVII) or a salt thereof.

In this reaction, compound (XXVI) or a salt thereof can be produced byreacting compound (XXVI) or a salt thereof with compound (XXXV) in thepresence of a base.

Examples of the base to be used for this reaction include silver salts(e.g., silver carbonate, silver nitrate, silver sulfate, silver acetate,silver chloride).

The amount of the silver salt to be used for this reaction is about 1 to5 mol equivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (XXVI).

This step can be performed in the same manner as in the method describedin Step 3 of Method C.

(Step 7)

This step is a step of subjecting compound (XXVII) or a salt thereof tohydrolysis to convert compound (XXVII) or a salt thereof to compound(XXVIII) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method B.

(Step 8)

This step is a step of reacting compound (XXVIII) or a salt thereof withcompound (VI) or a salt thereof in the presence of a condensing agent toproduce compound (XXIX) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method A or Step 1 of Method A.

(Step 9)

This step is a step of subjecting compound (XXIX) or a salt thereof to adeprotection reaction to produce compound (XXX) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 5 of Method B.

(Step 10)

This step is a step of subjecting compound (XXVI) or a salt thereof toan N-alkylation reaction to produce compound (XXXI) or a salt thereof.

In this reaction, compound (XXXI) or a salt thereof can be produced byreacting compound (XXVI) or a salt thereof with compound (XXXV) in thepresence of a base.

Examples of the base to be used for this reaction include cesium salts(e.g., cesium carbonate, cesium nitrate, cesium sulfate, cesium acetate,cesium chloride).

The amount of the cesium salt to be used for this reaction is about 1 to5 mol equivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (XXVI).

This step can be performed in the same manner as in the method describedin Step 3 of Method C.

(Step 11)

This step is a step of subjecting compound (XXXI) or a salt thereof tohydrolysis to convert compound (XXXI) or a salt thereof to compound(XXXII) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method B.

(Step 12)

This step is a step of reacting compound (XXXII) or a salt thereof withcompound (VI) or a salt thereof in the presence of a condensing agent toproduce compound (XXXIII) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method A or Step 1 of Method A.

(Step 13)

This step is a step of subjecting compound (XXXIII) or a salt thereof toa deprotection reaction to produce compound (XXXIV) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 5 of Method B.

A compound wherein

is CR^(5a)═CR⁶, R^(5a) is a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy),R⁶ is a hydrogen atom, Y is an oxygen atom, and W is a methylene groupin formula (Ia), which is a raw material compound in Method A, can beproduced according to Method E.

[Method E]

wherein each symbol is as defined above.

(Step 1)

This step is a step of subjecting compound (XXXVI) or a salt thereof toan alkylation reaction to produce compound (XXXVIII) or a salt thereof.

In this reaction, compound (XXXVIII) or a salt thereof can be producedby reacting compound (XXXVII) with N-bromosuccinimide (NBS) in thepresence of 2,2′-azobis(isobutyronitrile) (AIBN) (Step 1-1), and thenreacting the obtained compound with compound (XXXVI) or a salt thereofin the presence of a base (Step 1-2).

The amount of the AIBN to be used in Step 1-1 is about 0.001 to 0.5 molequivalent, preferably about 0.01 to 0.1 mol equivalent, per 1 mol ofcompound (XXXVII).

Compound (XXXVII) may be a commercially available product. The amountthereof to be used is about 1 to 5 mol equivalent, preferably about 1 to2 mol equivalent, per 1 mol of compound (XXXVI).

The amount of the NBS to be used in Step 1-1 is about 1 to 5 molequivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (XXXVII).

The solvent to be used in Step 1-1 is not particularly limited as longas it does not adversely influence the reaction, and examples thereofinclude hydrocarbons (benzene, toluene, xylene, etc.) and halogenatedhydrocarbons (trifluoromethylbenzene, chloroform, 1,2-dichloroethane,etc.).

The reaction temperature is generally about 0 to 200° C., preferablyabout 25 to 150° C., and the reaction time is generally about 0.5 to 48hr, preferably about 0.5 to 24 hr.

Examples of the base to be used in Step 1-2 include organic amines(trimethylamine, triethylamine, diisopropylethylamine,N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, pyridine,N,N-dimethylaniline, etc.). The amount thereof to be used is about 1 to5 mol equivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (XXXVI).

The solvent to be used in Step 1-2 is not particularly limited as longas it does not adversely influence the reaction, and examples thereofinclude hydrocarbons (benzene, toluene, xylene, etc.), halogenatedhydrocarbons (chloroform, 1,2-dichloroethane, etc.), nitriles(acetonitrile, etc.), ethers (dimethoxyethane, tetrahydrofuran), aproticpolar solvents (N,N-dimethylformamide, dimethyl sulfoxide,hexamethylphosphoroamide, etc.) and mixtures thereof. The reactiontemperature is generally about −10 to 200° C., preferably about 0 to 50°C., and the reaction time is generally about 0.5 to 48 hr, preferablyabout 0.5 to 24 hr.

(Step 2)

This step is a step of subjecting compound (XXXVIII) or a salt thereofto a cyclization reaction using chlorotrimethylsilane to producecompound (IXL) or a salt thereof.

The amount of the chlorotrimethylsilane to be used for this reaction isabout 1 to 5 mol equivalent, preferably about 1 to 2 mol equivalent, per1 mol of compound (XXXVIII).

The solvent to be used for this reaction is not particularly limited aslong as it does not adversely influence the reaction, and examplesthereof include hydrocarbons (benzene, toluene, xylene, etc.),halogenated hydrocarbons (chloroform, 1,2-dichloroethane, etc.),nitriles (acetonitrile, etc.) and ethers (dimethoxyethane,tetrahydrofuran). The reaction temperature is generally about 0 to 200°C., preferably about 25 to 100° C., and the reaction time is generallyabout 0.5 to 48 hr, preferably about 0.5 to 24 hr.

(Step 3)

This step is a step of subjecting compound (IXL) or a salt thereof to adebenzylation reaction to produce compound (XL) or a salt thereof.

The debenzylation reaction can be carried out in the presence of apalladium catalyst (e.g., palladium on carbon, palladium hydroxide,palladium oxide), in a solvent that does not adversely influence thereaction, under hydrogen atmosphere.

The amount of the palladium catalyst to be used is generally about 0.01to 1 mol equivalent, preferably about 0.05 to 0.2 mol equivalent, per 1mol of compound (IXL).

Examples of the solvent that does not adversely influence the reactioninclude alcohols (methanol, ethanol, propanol, 2-propanol, etc.), ethers(diethyl ether, 1,4-dioxane, tetrahydrofuran, etc.), nitriles(acetonitrile, etc.), hydrocarbons (benzene, toluene, etc.), esters(ethyl acetate, etc.) and the like, and they may be mixed asappropriate. The hydrogen pressure for the reaction is generally about 1to 50 atm, preferably about 1 to 10 atm. The reaction temperature isgenerally about 0 to 150° C., preferably about 10 to 30° C., and thereaction time is generally about 0.5 to 100 hr, preferably about 0.5 to60 hr.

(Step 4)

This step is a step of subjecting compound (XL) or a salt thereof to anacylation reaction or an ureation reaction to convert compound (XL) or asalt thereof to compound (XLI) or a salt thereof.

This step can be performed in the same manner as in the method describedin Steps 1 and 2 of Method A.

(Step 5)

This step is a step of subjecting compound (XLI) or a salt thereof tohydrolysis to convert compound (XLI) or a salt thereof to compound(XLII) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method B.

(Step 6)

This step is a step of subjecting compound (XL) or a salt thereof to anamino-protecting reaction to produce compound (XLIII) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 2 of Method B.

(Step 7)

This step is a step of subjecting compound (XLIII) or a salt thereof tohydrolysis to convert compound (XLIII) or a salt thereof to compound(XLIV) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method B.

(Step 8)

This step is a step of reacting compound (XLIV) or a salt thereof withcompound (VI) or a salt thereof in the presence of a condensing agent toproduce compound (XLV) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method A or Step 1 of Method A.

(Step 9)

This step is a step of subjecting compound (XLV) or a salt thereof to adeprotection reaction to produce compound (XLVI) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 5 of Method B.

When compound (VI) is a compound represented by the formula:

(hereinafter to be referred to as compound (XLVII)) or a salt thereof,the compound can be produced according to Method F.

[Method F]

(Step 1)

This step is a step of reacting compound (XLVIII) with a silylatingagent in the presence of or without a transition metal catalyst toproduce compound (XLIX).

Compound (XLVIII) may be a commercially available product.

Examples of the transition metal catalyst to be used for this reactioninclude palladium catalysts (palladium acetate, palladium chloride,tetrakistriphenylphosphinepalladium, etc.), nickel catalysts (nickelchloride, etc.) and the like. Where necessary, a ligand(triphenylphosphine, tri-tert-butylphosphine, S-Phos, BINAP, etc.) and abase (e.g., organic amines (trimethylamine, triethylamine,diisopropylamine, N-methylmorpholine,1,8-diazabicyclo[5,4,0]undec-7-ene, pyridine, N,N-dimethylaniline,etc.), alkali metal salts (sodium hydrogen carbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate,sodium phosphate, potassium phosphate, sodium hydroxide, potassiumhydroxide, etc.), metal hydrides (potassium hydride, sodium hydride,etc.), alkali metal alkoxides (sodium methoxide, sodium ethoxide, sodiumtert-butoxide, potassium tert-butoxide, etc.), alkali disilazides(lithium disilazide, sodium disilazide, potassium disilazide, etc.)) maybe added, or a metal oxide (copper oxide, silver oxide, etc.) and thelike my be used as a co-catalyst. The amount of the catalyst to be usedis about 0.0001 to 1 mol equivalent, preferably about 0.01 to 0.5 molequivalent, per 1 mol of compound (XLVIII). The amount of the ligand tobe used is about 0.0001 to 4 mol equivalent, preferably about 0.01 to 2mol equivalent, per 1 mol of compound (XLVIII). The amount of the baseto be used is about 1 to 10 mol equivalent, preferably about 1 to 2 molequivalent, per 1 mol of compound (XLVIII). The amount of theco-catalyst to be used is about 0.0001 to 4 mol equivalent, preferablyabout 0.01 to 2 mol equivalent, per 1 mol of compound (XLVIII).

Examples of the silylating agent include 1,1,1,2,2,2-hexamethyldisilaneand chlorotrimethylsilane.

The solvent to be used is not particularly limited as long as it doesnot adversely influence the reaction, and examples thereof includehydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons(chloroform, 1,2-dichloroethane, etc.), nitriles (acetonitrile, etc.),ethers (dimethoxyethane, tetrahydrofuran), alcohols (methanol, ethanol,etc.), aprotic polar solvents (N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoroamide, etc.), water and mixtures thereof.The reaction temperature is generally about −100 to 200° C., preferablyabout −80 to 150° C., and the reaction time is generally about 0.5 to 48hr, preferably about 0.5 to 24 hr. The reaction may be carried out undermicrowave irradiation, if necessary.

(Step 2)

This step is a step of subjecting compound (XLIX) to a reductionreaction using a transition metal catalyst to produce compound (XLVII).

Examples of the transition metal catalyst to be used for this reactioninclude palladiums (palladium on carbon, palladium hydroxide, palladiumoxide, etc.), nickels (Raney nickel, etc.), platinums (platinum oxide,platinum on carbon, etc.), rhodiums (rhodium acetate, rhodium on carbon,etc.) and the like. The amount thereof to be used is, for example, about0.001 to 1 equivalent, preferably about 0.01 to 0.5 equivalent, per 1mol of compound (XLIX). The catalytic hydrogenation reaction isgenerally carried out in a solvent inert to the reaction. Examples ofthe solvent include alcohols (methanol, ethanol, propanol, butanol,etc.), hydrocarbons (benzene, toluene, xylene, etc.), halogenatedhydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether,1,4-dioxane, tetrahydrofuran, etc.), esters (ethyl acetate, etc.),amides (N,N-dimethylformamide, etc.), carboxylic acids (acetic acid,etc.), water and mixtures thereof. The hydrogen pressure for thereaction is generally about 1 to 50 atm, preferably about 1 to 10 atm.The reaction temperature is generally about 0 to 150° C., preferablyabout 20 to 100° C., and the reaction time is generally about 5 min to72 hr, preferably about 0.5 to 40 hr.

When compound (VI) is a compound represented by the formula:

(hereinafter to be referred to as compound (L)) or a salt thereof, thecompound can be produced according to Method G.

[Method G]

(Step 1)

This step is a step of reacting compound (LI) with a silylating agent inthe presence of a transition metal catalyst to produce compound (LII).

Compound (LI) may be a commercially available product.

This step can be performed in the same manner as in the method describedin Step 1 of Method F.

(Step 2)

This step is a step of subjecting compound (LII) to a reduction reactionusing a transition metal catalyst to produce compound (L).

This step can be performed in the same manner as in the method describedin Step 2 of Method F.

When compound (X) is a compound represented by the formula:

wherein each symbol is as defined above (hereinafter to be referred toas compound (LIII)) or a salt thereof, the compound can be producedaccording to Method H.

[Method H]

wherein R¹⁰ is a trifluoromethyl group or a p-tolyl group, and the othersymbols are as defined above.

(Step 1)

This step is a step of subjecting compound (XVI) or a salt thereof to asulfonation reaction to produce compound (LIV) or a salt thereof.

Compound (XVI) may be a commercially available product, or can beproduced according to the above-mentioned Method B, a method known perse or a method analogous thereto.

This reaction can be carried out in the presence of a base and asulfonating agent.

Examples of the base to be used for this reaction include inorganicbases (alkali metal hydrides such as sodium hydride, lithium hydride andthe like, alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide, potassium hydroxide and the like, alkali metal hydrogencarbonates such as sodium hydrogen carbonate, potassium hydrogencarbonate and the like, alkali metal carbonates such as lithiumcarbonate, sodium carbonate, potassium carbonate, cesium carbonate andthe like, etc.), organic bases (amines such as trimethylamine,triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undec-7-eneand the like, cyclic amines such as pyridine, 4-dimethylaminopyridineand the like, etc.) and the like. While the amount of the base to beused varies depending on the kind of the solvent and the other reactioncondition, it is generally about 1 to 10 mol equivalent, preferablyabout 1 to 5 mol equivalent, per 1 mol of compound (XVI).

Examples of the sulfonating agent to be used for this reaction includesulfonyl chlorides (e.g., trifluoromethanesulfonyl chloride, p-tosylchloride), sulfonic anhydrides (e.g., trifluoromethanesulfonicanhydride, p-toluenesulfonic anhydride), sulfonimides (e.g.,N-phenylbis(trifluoromethanesulfonimide),N-(5-chloro-2-pyridyl)triflimide) and the like. While the amount of thesulfonating agent to be used varies depending on the kind of the solventand the other reaction condition, it is generally about 1 to 10 molequivalent, preferably about 1 to 5 mol equivalent, per 1 mol ofcompound (XVI).

This step is performed in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include aromatic hydrocarbons (benzene, toluene, xylene,etc.), aliphatic hydrocarbons (hexane, heptane, etc.), halogenatedhydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether,diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, etc.), nitriles (acetonitrile, etc.),esters (ethyl acetate, etc.), amides (N,N-dimethylformamide, etc.),sulfoxides (dimethyl sulfoxide, etc.) and the like. These solvent may beused in a mixture of two or more kinds thereof in an appropriate ratio.

The reaction temperature is, for example, within about −10 to 100° C.While the reaction time varies depending on the kind of compound (XVI)or a salt thereof, the reaction temperature and the like, it is, forexample, about 0.5 to 100 hr, preferably about 0.5 to 24 hr.

(Step 2)

This step is a step of subjecting compound (LIV) or a salt thereof to acyanation reaction to produce compound (LV) or a salt thereof.

The this reaction can be carried out using a cyanating agent in thepresence of a transition metal catalyst, in a solvent that does notadversely influence the reaction.

Examples of the transition metal catalyst to be used for this reactioninclude palladium catalysts (palladium acetate, palladium chloride,tetrakistriphenylphosphinepalladium, etc.), nickel catalysts (nickelchloride, etc.) and the like. Where necessary, a ligand(triphenylphosphine, tri-tert-butylphosphine, S-Phos, BINAP, etc.) canbe used. The amount of the transition metal catalyst to be used variesdepending on the kind of the solvent and the other reaction condition,it is generally about 0.001 to 1 mol equivalent, preferably about 0.1 to0.5 mol equivalent, per 1 mol of compound (LIV). The amount of theligand to be used is about 0.001 to 1 mol equivalent per 1 mol ofcompound (LIV).

Examples of the cyanating agent to be used for this reaction includezinc cyanide, copper cyanide and the like. The amount thereof to be usedvaries depending on the kind of the solvent and the other reactioncondition, it is generally about 0.5 to 10 mol equivalent, preferablyabout 0.5 to 2 mol equivalent, per 1 mol of compound (LIV).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons (benzene, toluene, xylene, etc.),aliphatic hydrocarbons (hexane, heptane, etc.), halogenated hydrocarbons(dichloromethane, chloroform, etc.), ethers (diethyl ether, diisopropylether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, etc.), nitriles (acetonitrile, etc.), esters (ethylacetate, etc.), amides (N,N-dimethylformamide, etc.), sulfoxides(dimethyl sulfoxide, etc.) and the like. These solvent may be used in amixture of two or more kinds thereof in an appropriate ratio.

The reaction temperature is, for example, within about −10 to 200° C.While the reaction time varies depending on the kind of compound (LIV)or a salt thereof, the reaction temperature and the like, it is, forexample, about 0.5 to 100 hr, preferably about 0.5 to 24 hr. Wherenecessary, the reaction may be carried out under microwave irradiation.

(Step 3)

This step is a step of subjecting compound (LV) or a salt thereof to areduction reaction to produce compound (LVI) or a salt thereof.

The reduction reaction can be carried out in the presence of aRaney-nickel catalyst, under hydrogen atmosphere or using a hydrogendonor.

The amount of the Raney-nickel catalyst to be used is generally about0.001 to 10 mol, preferably about 0.01 to 2 mol, per 1 mol of compound(LV).

The hydrogen pressure for the reaction is generally about 1 to 50 atm,preferably about 1 to 10 atm.

Examples of the hydrogen donor include sodium hypophosphite. The amountthereof to be used is generally about 1 to 100 mol, preferably about 1to 20 mol, per 1 mol of compound (LV).

This reaction is carried out in a solvent inert to the reaction.Examples of the solvent include alcohols such as methanol, ethanol,propanol, butanol and the like; hydrocarbons such as benzene, toluene,xylene and the like; halogenated hydrocarbons such as dichloromethane,chloroform and the like; ethers such as diethyl ether, 1,4-dioxane,tetrahydrofuran and the like; esters such as ethyl acetate and the like;amides such as N,N-dimethylformamide and the like;

carboxylic acids such as acetic acid and the like; bases such aspyridine, triethylamine and the like; water and mixtures thereof.

The reaction temperature is generally about 0° C. to 150° C., preferablyabout 20° C. to 100° C., and the reaction time is generally about 5 minto 72 hr, preferably about 0.5 hr to 40 hr.

(Step 4)

This step is a step of treating compound (LVI) or a salt thereof with areducing agent to produce compound (LVII) or a salt thereof.

Examples of the reducing agent to be used for this reaction includemetal hydrides (e.g., sodium borohydride, lithium borohydride, zincborohydride, sodium cyanoborohydride, sodium triacetoxyborohydride,lithium cyanoborohydride) and the like. The amount of the metal hydrideto be used is about 1 to 50 mol per 1 mol of compound (LVI).

This reaction is carried out in a solvent that does not adverselyinfluence the reaction. Examples of the solvent include alcohols such asmethanol, ethanol, propanol, butanol and the like; hydrocarbons such asbenzene, toluene, xylene and the like; halogenated hydrocarbons such asdichloromethane, chloroform and the like; ethers such as diethyl ether,1,4-dioxane, tetrahydrofuran and the like; esters such as ethyl acetateand the like; amides such as N,N-dimethylformamide and the like;carboxylic acids such as acetic acid and the like; water and mixturesthereof.

The reaction temperature is, for example, within about −50 to 200° C.,preferably about 0 to 50° C. While the reaction time varies depending onthe kind of compound (LVI), the reaction temperature and the like, itis, for example, about 0.1 to 100 hr, preferably about 0.1 to 6 hr.

(Step 5)

This step is a step of converting compound (LVII) or a salt thereof tocompound (LIII) or a salt thereof.

This step is a step of “reacting compound (LVII) or a salt thereof withcompound (XXXV) in the presence of a base to produce compound (LIII) ora salt thereof” or a step of “subjecting compound (LVII) or a saltthereof to a sulfonation reaction to convert compound (LVII) or a saltthereof to a compound represented by the formula:

wherein each symbol is as defined above (hereinafter to be referred toas compound (LVIIa)) or a salt thereof, and then reacting the compoundwith a compound represented by the formula:

R′—OH

wherein the symbol is as defined above (hereinafter to be referred to ascompound (XXXVa)) or a salt thereof in the presence of a base to producecompound (LIII) or a salt thereof”.

The method of “reacting compound (LVII) or a salt thereof with compound(XXXV) in the presence of a base to produce compound (LIII) or a saltthereof” can be carried out in the same manner as in the methoddescribed in Step 3 of Method C.

The sulfonation reaction in the method of “subjecting compound (LVII) ora salt thereof to a sulfonation reaction to convert compound (LVII) or asalt thereof to compound (LVIIa) or a salt thereof, and then reactingcompound (LVIIa) or a salt thereof with compound (XXXVa) or a saltthereof in the presence of a base to produce compound (LIII) or a saltthereof” can be carried out in the same manner as in the methoddescribed in Step 1 of Method H.

Examples of the base to be used for the reaction of compound (LVIIa) ora salt thereof with compound (XXXVa) or a salt thereof in the presenceof a base include organic amines (trimethylamine, triethylamine,diisopropylamine, N-methylmorpholine,1,8-diazabicyclo[5,4,0]undec-7-ene, pyridine, N,N-dimethylaniline,etc.), alkali metal salts (sodium hydrogen carbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate,sodium phosphate, potassium phosphate, sodium hydroxide, potassiumhydroxide, lithium acetate, etc.), metal hydrides (potassium hydride,sodium hydride, etc.) and the like. The amount of the base to be used isabout 1 to 10 mol equivalent per 1 mol of compound (LVIIa).

This step is performed in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include hydrocarbons (benzene, toluene, xylene, etc.),halogenated hydrocarbons (chloroform, 1,2-dichloroethane, etc.),nitriles (acetonitrile, etc.), ethers (dimethoxyethane,tetrahydrofuran), aprotic polar solvents (N,N-dimethylformamide,dimethyl sulfoxide, hexamethylphosphoroamide, etc.) and mixturesthereof. Compound (XXXVa) itself may be used as a solvent. The reactiontemperature is generally about −100 to 200° C., preferably about −20 to100° C., and the reaction time is generally about 0.5 to 48 hr,preferably about 0.5 to 24 hr.

When compound (VI) is a compound represented by the formula:

(hereinafter to be referred to as compound (LVIII)) or a salt thereof,the compound can be produced according to Method I.

[Method I]

wherein the symbol is as defined above.

(Step 1)

This step is a step of subjecting compound (LIX) to a demethylationreaction to produce compound (LX).

Compound (LIX) may be a commercially available product, or can also beproduced according to a method known per se or a method analogousthereto.

The demethylation reaction can be carried out according to a methodknown per se (e.g., the method described in “Protective Groups inOrganic Synthesis, 3rd Ed”, Wiley-Interscience, Inc. (1999) (Theodora W.Greene, Peter G. M. Wuts)). For example, compound (LX) can be producedby treating compound (LIX) with aluminium chloride in the presence of1-dodecanethiol.

The amount of the 1-dodecanethiol to be used is about 1 to 10 molequivalent per 1 mol of compound (LIX). The amount of the aluminiumchloride to be used is about 1 to 10 mol equivalent per 1 mol ofcompound (LIX).

This reaction is carried out in a solvent that does not adverselyinfluence the reaction. Examples of the solvent include hydrocarbonssuch as benzene, toluene, xylene and the like; halogenated hydrocarbonssuch as dichloromethane, chloroform and the like; ethers such as diethylether, 1,4-dioxane, tetrahydrofuran and the like; and the like.

The reaction temperature is, for example, within about −50 to 100° C.,preferably about −10 to 50° C. While the reaction time varies dependingon the reaction temperature and the like, it is, for example, about 0.1to 100 hr, preferably about 0.1 to 6 hr.

(Step 2)

This step is a step of subjecting compound (LX) or a salt thereof to asulfonation reaction to produce compound (LXI) or a salt thereof. Thisstep can be performed in the same manner as in the method described inStep 1 of Method H.

(Step 3)

This step is a step of reacting compound (LXI) with an aminating agentin the presence of a transition metal catalyst and a base, and thentreating the resulting compound with an acid or a combination ofhydroxyamine hydrochloride and sodium acetate to produce compound(LVIII).

Examples of the transition metal catalyst to be used for this reactioninclude palladium catalysts (palladium acetate, palladium chloride,tetrakistriphenylphosphinepalladium,tris(dibenzylideneacetone)dipalladium (0), etc.), nickel catalysts(nickel chloride, etc.) and the like. Where necessary, a ligand(triphenylphosphine, tri-tert-butylphosphine, S-Phos, BINAP,2′-(di-tert-butylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine,XANTPHOS, etc.) or a base (e.g., organic amines (trimethylamine,triethylamine, diisopropylamine, N-methylmorpholine,1,8-diazabicyclo[5,4,0]undec-7-ene, pyridine, N,N-dimethylaniline,etc.), alkali metal salts (sodium hydrogen carbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate,sodium phosphate, potassium phosphate, sodium hydroxide, potassiumhydroxide, lithium acetate, etc.), metal hydrides (potassium hydride,sodium hydride, etc.), alkali metal alkoxides (sodium methoxide, sodiumethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.) andalkali disilazides (lithium disilazide, sodium disilazide, potassiumdisilazide, etc.)) may be added. A metal oxide (copper oxide, silveroxide, etc.) and the like may be used as a co-catalyst. The amount ofthe catalyst to be used is about 0.0001 to 1 mol equivalent, preferablyabout 0.01 to 0.5 mol equivalent, per 1 mol of compound (LXI). Theamount of the ligand to be used is about 0.0001 to 4 mol equivalent,preferably about 0.01 to 2 mol equivalent, per 1 mol of compound (LXI).The amount of the base to be used is about 1 to 10 mol equivalent,preferably about 1 to 2 mol equivalent, per 1 mol of compound (LXI). Theamount of the co-catalyst to be used is about 0.0001 to 4 molequivalent, preferably about 0.01 to 2 mol equivalent, per 1 mol ofcompound (LXI).

This step is performed in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include hydrocarbons (benzene, toluene, xylene, etc.),halogenated hydrocarbons (chloroform, 1,2-dichloroethane, etc.),nitriles (acetonitrile, etc.), ethers (dimethoxyethane,tetrahydrofuran), alcohols (methanol, ethanol, etc.), aprotic polarsolvents (N,N-dimethylformamide, dimethyl sulfoxide,hexamethylphosphoroamide, etc.), water and mixtures thereof. Thereaction temperature is generally about −100 to 200° C., preferablyabout −80 to 150° C., and the reaction time is generally about 0.5 to 48hr, preferably about 0.5 to 24 hr.

Preferable examples of the aminating agent to be used includediphenylmethanimine. The amount of the aminating agent to be used isabout 1 to 5 mol equivalent, preferably about 1 to 2 mol equivalent, per1 mol of compound (LXI).

Examples of the acid to be used include mineral acids (hydrochloricacid, hydrobromic acid, sulfuric acid, etc.). While the amount of theacid to be used varies depending on the kind of the solvent and theother reaction condition, it is generally about 0.1 mol equivalent ormore per 1 mol of compound (LXI). Preferable examples of the solvent tobe used include THF and water. The reaction temperature is about −20 to100° C., preferably about 0 to 30° C., and the reaction time isgenerally about 1 to 100 hr, preferably about 1 to 72 hr.

The amount of the hydroxyamine hydrochloride and sodium acetate to beused is about 1 to 5 mol equivalent, preferably about 1 to 2 molequivalent, per 1 mol of compound (LXI), respectively.

Preferable examples of the solvent to be used for the treatment withhydroxyamine hydrochloride and sodium acetate include methanol. Thereaction temperature is about −20 to 100° C., preferably about 0 to 30°C., and the reaction time is generally about 1 to 100 hr, preferablyabout 1 to 72 hr.

When compound (VI) is a compound represented by the formula:

(hereinafter to be referred to as compound (LXII)) or a salt thereof,the compound can be produced according to Method J.

[Method J]

wherein the symbol is as defined above.

(Step 1)

This step is a step of subjecting compound (LXIII) or a salt thereof toa sulfonation reaction to produce compound (LXIV) or a salt thereof.

Compound (LXIII) can be produced according to a method known per se or amethod analogous thereto.

This step can be performed in the same manner as in the method describedin Step 2 of Method H.

(Step 2)

This step is a step of reacting compound (LXIV) with an aminating agentin the presence of a transition metal catalyst and a base, and thentreating the resulting compound with an acid or a combination ofhydroxyamine hydrochloride and sodium acetate to produce compound(LXII).

This step can be performed in the same manner as in the method describedin Step 3 of Method I.

When compound (VI) is a compound represented by the formula:

(hereinafter to be referred to as compound (LXV)) or a salt thereof, thecompound can be produced according to Method K.

[Method K]

(Step 1)

This step is a step of subjecting compound (LXVI) to methylation toproduce compound (LXVII).

In this reaction, compound (LXVII) can be produced by reacting compound(LXVI) with iodomethane in the presence of a base.

Compound (LXVI) may be a commercially available product, or can also beproduced according to a method known per se or a method analogousthereto.

Examples of the base to be used for this reaction include alkali metalhydrides (e.g., sodium hydride, lithium hydride). While the amount ofthe base to be used varies depending on the kind of the solvent and theother reaction condition, it is generally about 2 to 10 mol equivalent,preferably about 2 to 5 mol equivalent, per 1 mol of compound (LXVI).

The amount of the iodomethane to be used is generally about 2 to 10 molequivalent, preferably about 2 to 3 mol equivalent, per 1 mol ofcompound (LXVI).

This step is performed in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include aromatic hydrocarbons (benzene, toluene, xylene,etc.), aliphatic hydrocarbons (hexane, heptane, etc.), halogenatedhydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether,diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, etc.), nitriles (acetonitrile, etc.),esters (ethyl acetate, etc.), amides (N,N-dimethylformamide, etc.),sulfoxides (dimethyl sulfoxide, etc.) and the like. These solvent may beused in a mixture of two or more kinds thereof in an appropriate ratio.

The reaction temperature is, for example, within about −75 to 100° C.,preferably about −10 to 30° C. While the reaction time varies dependingon the reaction temperature and the like, it is, for example, about 0.5to 100 hr, preferably about 0.5 to 24 hr.

(Step 2)

This step is a step of subjecting compound (LXVII) to a reductionreaction using a transition metal catalyst to produce compound (LXV).

This step can be performed in the same manner as in the method describedin Step 2 of Method F.

When compound (VI) is a compound represented by the formula:

wherein the symbol is as defined above (hereinafter to be referred to ascompound (LXVIII)) or a salt thereof, the compound can be producedaccording to Method L.

[Method L]

wherein the symbol is as defined above.

(Step 1)

This step is a step of treating compound (LXVII) with a reducing agentto produce compound (LXIX).

Compound (LXVII) may be a commercially available product, or can also beproduced according to a method known per se or a method analogousthereto.

Examples of the reducing agent to be used for this reaction includemetal hydrides (e.g., lithium borohydride, diisobutylaluminium hydride,aluminium hydride, lithium aluminium hydride). The amount of the metalhydride to be used is about 0.5 to 50 mol per 1 mol of compound (LXVII).

This step is performed in a solvent that does not adversely influencethe reaction, and examples of the solvent that does not adverselyinfluence the reaction include aromatic hydrocarbons (benzene, toluene,xylene, etc.), aliphatic hydrocarbons (hexane, heptane, etc.),halogenated hydrocarbons (dichloromethane, chloroform, etc.), ethers(diethyl ether, diisopropyl ether, tert-butyl methyl ether,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.) and the like.These solvent may be used in a mixture of two or more kinds thereof inan appropriate ratio.

The reaction temperature is generally about −20 to 100° C., preferablyabout 0 to 30° C., and the reaction time is generally about 1 to 100 hr,preferably about 1 to 72 hr.

(Step 2)

This step is a step of subjecting compound (LXIX) to an alkylationreaction with compound (XXXV) in the presence of a base to producecompound (LXX) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method C.

(Step 3)

This step is a step of subjecting compound (LXX) to a reduction reactionusing a transition metal catalyst to produce compound (LXVIII).

This step can be performed in the same manner as in the method describedin Step 2 of Method F.

When compound (VI) is a compound represented by the formula:

(hereinafter to be referred to as compound (LXXI)) or a salt thereof,the compound can be produced according to Method M.

[Method M]

(Step 1)

This step is a step of reacting compound (LXXII) with a silylating agentin the presence of a transition metal catalyst to produce compound(LXXIII).

Compound (LXXII) may be a commercially available product.

This step can be performed in the same manner as in the method describedin Step 1 of Method G.

(Step 2)

This step is a step of subjecting compound (LXXIII) to a reductionreaction using a transition metal catalyst to produce compound (LXXI).

This step can be performed in the same manner as in the method describedin Step 2 of Method G.

When compound (VI) is a compound represented by the formula:

(hereinafter to be referred to as compound (LXXIV)) or a salt thereof,the compound can be produced according to Method N.

[Method N]

(Step 1)

This step is a step of reacting compound (XLVIII) with a silylatingagent in the presence of or without a transition metal catalyst toproduce compound (LXXV).

Compound (XLVIII) may be a commercially available product.

This step can be performed in the same manner as in the method describedin Step 1 of Method F.

Examples of the silylating agent include chloro(ethyl)dimethylsilane.

(Step 2)

This step is a step of subjecting compound (LXXV) to a reductionreaction using a transition metal catalyst to produce compound (LXXIV).

This step can be performed in the same manner as in the method describedin Step 2 of Method G.

When compound (VI) is a compound represented by the formula:

(hereinafter to be referred to as compound (LXXVI)) or a salt thereof,the compound can be produced according to Method O.

[Method O]

wherein PMB is a 4-methoxybenzyl group, and the other symbols are asdefined above.

(Step 1)

This step is a step of subjecting compound (LXXVII) to a couplingreaction with diethyl malonate in the presence of a base to convertcompound (LXXVII) to compound (LXXVIII).

Compound (LXXVII) may be a commercially available product.

Examples of the base to be used for this reaction include organiclithium reagents (e.g., n-butyllithium, phenyllithium, lithiumdiisopropylamide), alkali metal hydrides (e.g., sodium hydride, lithiumhydride) and the like. While the amount of the base to be used variesdepending on the kind of the solvent and the other reaction condition,it is generally about 1 to 10 mol equivalent, preferably about 1 to 2mol equivalent, per 1 mol of compound (LXXVII).

The amount of the diethyl malonate to be used for this reaction is about1 to 10 mol equivalent, preferably about 1 to 5 mol equivalent, per 1mol of compound (LXXVII).

This step is performed in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include aromatic hydrocarbons (benzene, toluene, xylene,etc.), aliphatic hydrocarbons (hexane, heptane, etc.), halogenatedhydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether,diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, etc.), amides (N,N-dimethylformamide,etc.) and the like. These solvent may be used in a mixture of two ormore kinds thereof in an appropriate ratio.

The reaction temperature is, for example, within about −100 to 50° C.,preferably about −78 to 25° C., and the reaction time is, for example,about 0.5 to 100 hr, preferably about 0.5 to 24 hr.

(Step 2)

This step is a step of subjecting compound (LXXVIII) to a hydrolysisreaction and decarboxylation reaction to convert compound (LXXVIII) tocompound (LXXIX) or a salt thereof.

The hydrolysis reaction can be carried out in the same manner as in themethod described in Step 3 of Method B. The decarboxylation reactionprogresses rapidly without stopping halfway after the hydrolysisreaction.

(Step 3)

This step is a step of subjecting compound (LXXIX) or a salt thereof tomethyl esterification to produce compound (LXXX).

This reaction can be carried out according to a method known per se(e.g., the method described in “Protective Groups in Organic Synthesis,3rd Ed”, Wiley-Interscience, Inc. (1999) (Theodora W. Greene, Peter G.M. Wuts)). For example, compound (LXXX) can be produced by heatingcompound (LXXIX) or a salt thereof in methanol, in the presence of anacid catalyst.

Examples of the acid catalyst to be used for this reaction includemineral acids (hydrochloric acid, sulfuric acid, etc.), organic sulfonicacids (methanesulfonic acid, p-toluenesulfonic acid, etc.), Lewis acids(boron fluoride etherate, etc.), thionyl chloride and the like. Whilethe amount of the acid catalyst to be used varies depending on the kindof the solvent and the other reaction condition, it is generally about0.0001 to 10 mol equivalent, preferably about 0.01 to 0.1 molequivalent, per 1 mol of compound (LXXIX).

In this reaction, methanol may be used as a solvent. The reactiontemperature is, for example, within about 0 to 120° C., preferably about25 to 80° C., and the reaction time is, for example, about 0.5 to 100hr, preferably about 0.5 to 24 hr.

(Step 4)

This step is a step of subjecting compound (LXXX) to methylation toproduce compound (LXXXI).

This step can be performed in the same manner as in the method describedin Step 1 of Method K.

(Step 5)

This step is a step of subjecting compound (LXXXI) to a reductionreaction using a transition metal catalyst to produce compound (LXXXII).

This step can be performed in the same manner as in the method describedin Step 2 of Method G.

(Step 6)

This step is a step of reacting compound (LXXXII) withα-chloro-4-methoxytoluene in the presence of a base to produce compound(LXXXIII).

Examples of the base to be used for this reaction include inorganicbases (alkali metal hydrides such as sodium hydride, lithium hydride andthe like, alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide, potassium hydroxide and the like, alkali metal hydrogencarbonates such as sodium hydrogen carbonate, potassium hydrogencarbonate and the like, alkali metal carbonates such as lithiumcarbonate, sodium carbonate, potassium carbonate, cesium carbonate andthe like, alkali metal alkoxides such as sodium methoxide, sodiumethoxide and the like, etc.), organic bases (amines such astrimethylamine, triethylamine, diisopropylethylamine and the like,cyclic amines such as pyridine, 4-dimethylaminopyridine and the like,etc.) and the like. While the amount of the base to be used variesdepending on the kind of the solvent and the other reaction condition,it is generally about 2 to 10 mol equivalent, preferably about 2 to 5mol equivalent, per 1 mol of compound (LXXXII).

The amount of the α-chloro-4-methoxytoluene to be used is about 2 to 10mol equivalent, preferably about 2 to 5 mol equivalent, per 1 mol ofcompound (LXXXII).

This step is performed in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include aromatic hydrocarbons (benzene, toluene, xylene,etc.), aliphatic hydrocarbons (hexane, heptane, etc.), halogenatedhydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether,diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, etc.), amides (N,N-dimethylformamide,etc.) and the like. These solvent may be used in a mixture of two ormore kinds thereof in an appropriate ratio.

The reaction temperature is, for example, within about −100 to 150° C.,preferably about −78 to 50° C., and the reaction time is, for example,about 0.5 to 100 hr, preferably about 0.5 to 24 hr.

This reaction can also be carried out under the condition described in“when the amino group is protected by a PMB group” in Step 2 of MethodB.

(Step 7)

This step is a step of treating compound (LXXXIII) with a reducing agentto produce compound (LXXXIV).

This step can be performed in the same manner as in the method describedin Step 1 of Method L.

(Step 8)

This step is a step of subjecting compound (LXXXIV) to an alkylationreaction with compound (XXXV) in the presence of a base to producecompound (LXXXV) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method C.

(Step 9)

This step is a step of subjecting compound (LXXXV) or a salt thereof toa deprotection reaction to produce compound (LXXV) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 5 of Method B.

When compound (VI) is a compound represented by the formula:

(hereinafter to be referred to as compound (LXXXVIII)) or a saltthereof, the compound can be produced according to Method P.

[Method P]

(Step 1)

This step is a step of subjecting compound (LXXXI) or a salt thereof tohydrolysis to convert compound (LXXXI) or a salt thereof to compound(LXXXVI) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method B.

(Step 2)

This step is a step of reacting compound (LXXXVI) or a salt thereof withpyrrolidine or a salt thereof in the presence of a condensing agent toproduce compound (LXXXVII) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method A or Step 1 of Method A.

(Step 3)

This step is a step of subjecting compound (LXXXVII) to a reductionreaction using a transition metal catalyst to produce compound(LXXXVIII).

This step can be performed in the same manner as in the method describedin Step 2 of Method G.

When compound (XII) is a compound represented by the formula:

wherein each symbol is as defined above (hereinafter to be referred toas compound (LXLIV)) or a salt thereof, the compound can be producedaccording to Method Q.

[Method Q]

wherein the symbol is as defined above.

(Step 1)

This step is a step of subjecting compound (XXVI) or a salt thereof to asulfonation reaction to produce compound (LXXXIX) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 1 of Method H.

(Step 2)

This step is a step of subjecting compound (LXXXIX) or a salt thereof toa cyanation reaction to produce compound (LXL) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 2 of Method H.

(Step 3)

This step is a step of subjecting compound (LXL) or a salt thereof tohydrolysis to produce compound (LXLI) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method B.

(Step 4)

This step is a step of reacting compound (LXLI) or a salt thereof withcompound (VI) or a salt thereof in the presence of a condensing agent toproduce compound (LXLII) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method A or Step 1 of Method A.

(Step 5)

This step is a step of treating compound (LXLII) or a salt thereof witha reducing agent to produce compound (LXLIII) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 1 of Method L.

(Step 6)

This step is a step of converting compound (LXLIII) or a salt thereof tocompound (LXLIV) or a salt thereof.

This step is a step of “reacting compound (LXLIII) or a salt thereofwith compound (XXXV) in the presence of a base to produce compound(LXLIV) or a salt thereof” or a step of “subjecting compound (LXLIII) ora salt thereof to a sulfonation reaction to convert compound (LXLIII) ora salt thereof to a compound represented by the formula:

wherein each symbol is as defined above (hereinafter to be referred toas compound (LXLIIIa)) or a salt thereof, and reacting the compound witha compound represented by the formula:

R⁹—OH

wherein the symbol is as defined above (hereinafter to be referred to ascompound (XXXVa)) or a salt thereof in the presence of a base to producecompound (LXLIV) or a salt thereof”.

This step can be performed in the same manner as in the method describedin Step 5 of Method H.

When compound (VI) is a compound represented by the formula:

(hereinafter to be referred to as compound (LXLVIII)) or a salt thereof,the compound can be produced according to Method R.

[Method R]

(Step 1)

This step is a step of subjecting compound (LXLV) to a nitrationreaction to produce compound (LXLVI).

Compound (LXLV) may be a commercially available product, or can also beproduced according to a method known per se or a method analogousthereto.

In this reaction, compound (LXLVI) can be produced by reacting compound(LXLV) with conc. nitric acid in the presence of conc. sulfuric acid.

The conc. sulfuric acid to be used for this reaction is used as asolvent, and the amount thereof is generally about 1 to 10 molequivalent per 1 mol of compound (LXLV). The amount of the conc. nitricacid is generally about 1 to 2 mol equivalent, preferably about 1 to 1.1mol equivalent, per 1 mol of compound (LXLV). The reaction temperatureis, for example, −10° C. to 50° C., preferably 0 to 25° C. The reactiontime is, for example, 0.5 to 24 hr, preferably 0.5 to 2 hr.

(Step 2)

This step is a step of reacting compound (LXLVI) with a silylating agentin the presence of or without a transition metal catalyst to producecompound (LXLVII).

This step can be performed in the same manner as in the method describedin Step 1 of Method F.

Examples of the silylating agent include chlorotrimethylsilane.

(Step 3)

This step is a step of subjecting compound (LXLVII) to a reductionreaction using a transition metal catalyst to produce compound(LXLVIII).

This step can be performed in the same manner as in the method describedin Step 2 of Method G.

When compound (X) is a compound represented by the formula:

wherein each symbol is as defined above (hereinafter to be referred toas compound (Xa)) or a salt thereof, the compound can be producedaccording to Method S.

[Method S]

wherein the symbol is as defined above.

(Step 1)

This step is a step of subjecting compound (LIVa) or a salt thereof to aborate esterification reaction to convert compound (LIVa) or a saltthereof to compound (LXLIX) or a salt thereof.

This reaction can be carried out in the presence of a transition metalcatalyst, bis(pinacolato)diboron and a base, in a solvent that does notadversely influence the reaction.

Examples of the transition metal catalyst to be used include palladiumcatalysts (1,1′-bis(diphenylphosphino) ferrocene-palladium(II)dichloride-dichloromethane complex, palladium acetate, palladiumchloride, tetrakistriphenylphosphinepalladium, etc.), nickel catalysts(nickel chloride, etc.) and the like. Where necessary, a ligand(triphenylphosphine, tri-tert-butylphosphine, S-Phos, etc.) may beadded. A metal oxide (copper oxide, silver oxide, etc.) and the like maybe used as a co-catalyst. While the amount of the catalyst to be usedvaries depending on the kind of the catalyst, it is generally about0.0001 to 1 mol equivalent, preferably about 0.01 to 0.5 mol equivalent,per 1 mol of compound (LIVa). The amount of the ligand to be used isgenerally about 0.0001 to 4 mol equivalent, preferably about 0.01 to 2mol equivalent, per 1 mol of compound (LIVa). The amount of theco-catalyst to be used is about 0.0001 to 4 mol equivalent, preferablyabout 0.01 to 2 mol equivalent, per 1 mol of compound (LIVa).

The amount of the bis(pinacolato)diboron to be used is about 1 to 5 molequivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (LIVa).

Examples of the base to be used include organic amines (trimethylamine,triethylamine, diisopropylamine, N-methylmorpholine,1,8-diazabicyclo[5,4,0]undec-7-ene, pyridine, N,N-dimethylaniline,etc.), alkali metal salts (sodium hydrogen carbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate,sodium phosphate, potassium acetate, potassium phosphate, sodiumhydroxide, potassium hydroxide, etc.), metal hydrides (potassiumhydride, sodium hydride, etc.), alkali metal alkoxides (sodiummethoxide, sodium ethoxide, sodium tert-butoxide, potassiumtert-butoxide, etc.), alkali disilazides (lithium disilazide, sodiumdisilazide, potassium disilazide, etc.) and the like. Among them, alkalimetal salts such as potassium acetate and the like are preferable. Theamount of the base to be used is about 0.1 to 10 mol equivalent,preferably about 1 to 5 mol equivalent, per 1 mol of compound (LIVa).

The solvent to be used is not particularly limited as long as it doesnot adversely influence the reaction, and examples thereof includehydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons(chloroform, 1,2-dichloroethane, etc.), nitriles (acetonitrile, etc.),ethers (dimethoxyethane, tetrahydrofuran), alcohols (methanol, ethanol,etc.), aprotic polar solvents (N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoroamide, etc.), water and mixtures thereof.The reaction temperature is generally −10 to 200° C., preferably about 0to 150° C., and the reaction time is generally 0.5 to 48 hr, preferably0.5 to 24 hr.

(Step 2)

This step is a step of subjecting compound (LXLIX) or a salt thereof tohydrolysis, and then subjecting the resulting compound to a mesylationreaction to convert compound (LXLIX) or a salt thereof to compound (Xa)or a salt thereof. The reaction of subjecting compound (LXLIX) or a saltthereof to hydrolysis can be carried out using sodium periodate in asolvent that does not adversely influence the reaction.

The amount of the sodium periodate to be used is about 1 to 10 molequivalent, preferably about 1 to 3 mol equivalent, per 1 mol ofcompound (LXLIX).

The solvent to be used is not particularly limited as long as it doesnot adversely influence the reaction, and examples thereof includewater, ketones (acetone, methylethylketone, etc.), nitriles(acetonitrile, etc.), ethers (dimethoxyethane, tetrahydrofuran),alcohols (methanol, ethanol, etc.), aprotic polar solvents(N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoroamide,etc.) and mixtures thereof. The reaction temperature is generally −10 to100° C., preferably about 0 to 25° C., and the reaction time isgenerally 0.5 to 48 hr, preferably 0.5 to 24 hr.

The mesylation reaction can be carried out in the presence of copper(II)acetate and sodium methanesulfinate, in l-butyl-3-methylimidazoliumtrifluoromethylsulfonate.

The amount of the copper(II) acetate to be used is about 0.01 to 1 molequivalent, preferably about 0.01 to 0.1 mol equivalent, per 1 mol ofcompound (LXLIX).

The amount of the sodium methanesulfinate to be used is about 1 to 5 molequivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (LXLIX). The amount of the 1-butyl-3-methylimidazoliumtrifluoromethylsulfonate to be used is about 1 to 10 mol equivalent,preferably about 1 to 5 mol equivalent, per 1 mol of compound (LXLIX).The reaction temperature is generally −10 to 150° C., preferably about 0to 100° C., and the reaction time is generally 0.5 to 48 hr, preferably0.5 to 24 hr.

When compound (I) is a compound represented by the formula

wherein each symbol is as defined above (hereinafter to be referred toas compound (Ib)), or a compound represented by the formula

wherein each symbol is as defined above (hereinafter to be referred toas compound (Ic)), or a compound represented by the formula:

wherein each symbol is as defined above (hereinafter to be referred toas compound (Id)), or a compound represented by the formula:

wherein each symbol is as defined above (hereinafter to be referred toas compound (Ie)), compounds (Ib), (Ic), (Id) and (Ie) or a salt thereofof the present invention can be produced according to the followingMethod T.

[Method T]

wherein each symbol is as defined above.

Compound (IIa) can be produced according to the below-mentioned MethodU.

(Step 1)

This step is a step of subjecting compound (IIa) or a salt thereof to anacylation reaction to convert compound (IIa) or a salt thereof tocompound (Ib) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 1 of Method A.

(Step 2)

This step is a step of subjecting compound (IIa) or a salt thereof to anureation reaction to convert compound (IIa) or a salt thereof tocompound (Ib) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 2 of Method A.

(Step 3)

This step is a step of reacting compound (IIa) or a salt thereof with acompound represented by the formula

wherein each symbol is as defined above (hereinafter to be referred toas compound (C)) or a salt thereof in the presence of a base to producecompound (Ic) or a salt thereof.

Compound (C) or a salt thereof may be a commercially available product,or can also be produced according to a method known per se or a methodanalogous thereto.

In this reaction, the amount of compound (C), the kind and amount of thebase to be used, the kind and amount of the solvent to be used, thereaction temperature and the reaction time can be selected from thosedescribed in Step 1 of Method A.

(Step 4)

This step is a step of subjecting compound (IIa) or a salt thereof to analkylation reaction to convert compound (IIa) or a salt thereof tocompound (Id) or a salt thereof.

This step is a step of subjecting compound (IIa) or a salt thereof to analkylation reaction with a compound represented by the formula

wherein each symbol is as defined above (hereinafter to be referred toas compound (CI)) or a salt thereof in the presence of a base to producecompound (Id) or a salt thereof.

Compound (CI) may be a commercially available product, or can also beproduced according to a method known per se or a method analogousthereto.

This step can be performed in the same manner as in the method describedin Step 3 of Method C.

(Step 5)

This step is a step of subjecting compound (IIa) or a salt thereof to areductive alkylation reaction to convert compound (IIa) or a saltthereof to compound (Ie) or a salt thereof.

This step is a step of reacting compound (IIa) or a salt thereof with acompound represented by the formula

wherein each symbol is as defined above (hereinafter to be referred toas compound (CII)) or a salt thereof in the presence of a reducing agentto produce compound (Ie) or a salt thereof.

The reductive alkylation reaction in this step can be carried outaccording to a method known per se. For example, the reaction can becarried out by reacting compound (IIa) or a salt thereof with compound(CII) or a salt thereof, and then subjecting the resulting imine oriminium ion to a reduction reaction.

The amount of compound (CII) to be used is generally about 1 to 10 molequivalent, preferably about 1 to 3 mol equivalent, per 1 mol ofcompound (IIa).

The solvent to be used for the production reaction of the imine oriminium ion is not particularly limited as long as the reactionproceeds, and examples thereof include hydrocarbons (heptane, hexane,toluene, xylene, etc.), halogenated hydrocarbons (chloroform,dichloromethane, 1,2-dichloroethane, etc.), ethers (diethyl ether,tetrahydrofuran, 1,4-dioxane, etc.), esters (ethyl acetate, tert-butylacetate, etc.), alcohols (methanol, ethanol, 2-propanol, etc.), nitriles(acetonitrile, butyronitrile, etc.), amides (N,N-dimethylformamide,N,N-dimethylacetamide, etc.), sulfoxides (dimethyl sulfoxide, etc.) andmixed solvents thereof.

In this step, the reaction can advantageously proceeds by the additionof a catalyst, if necessary. Examples of the catalyst include mineralacids (hydrochloric acid, hydrobromic acid, sulfuric acid, etc.),carboxylic acids (formic acid, acetic acid, propionic acid,trifluoroacetic acid, etc.), sulfonic acids (methanesulfonic acid,p-toluenesulfonic acid, etc.), Lewis acids (aluminium chloride, zincchloride, zinc bromide, boron trifluoride, titanium chloride, etc.),acetates (sodium acetate, potassium acetate, etc.), molecular sieves(molecular sieves 3A, 4A, 5A, etc.), dehydrating agents (magnesiumsulfate, etc.) and the like. The amount of the catalyst to be used isgenerally 0.01 to 50 mol equivalent, preferably about 0.1 to about 10mol, per 1 mol of compound (IIa).

The reaction temperature is generally about 0° C. to about 200° C.,preferably about 20° C. to about 150° C., and the reaction time isgenerally about 0.5 hr to about 48 hr, preferably about 0.5 hr to about24 hr.

The conversion to the imine or iminium ion can be carried out accordingto various reduction reactions in a solvent. The reduction reaction canbe carried out according to a method known per se, and examples thereofinclude a method using a metal hydride, and method employing catalytichydrogenation reaction.

Examples of the metal hydride include sodium borohydride, lithiumborohydride, zinc borohydride, sodium cyanoborohydride, sodiumtriacetoxyborohydride, lithium cyanoborohydride, dibutylaluminiumhydride, aluminium hydride, lithium aluminium hydride, borane complex(borane-THF complex, catecholborane, etc.) and the like. Among them,sodium borohydride, sodium cyanoborohydride, sodiumtriacetoxyborohydride and the like are preferable. The amount of themetal hydride to be used is, for example, about 1 to about 50 mol,preferably about 1 to about 10 mol, per 1 mol of the imine.

The reduction reaction using a metal hydride is generally carried out ina solvent inert to the reaction. Examples of the solvent includearomatic hydrocarbons (toluene, xylene, etc.), aliphatic hydrocarbons(heptane, hexane, etc.), halogenated hydrocarbons (chloroform,dichloromethane, etc.), ethers (diethyl ether, tetrahydrofuran,1,4-dioxane, etc.), alcohols (methanol, ethanol, 2-propanol, butanol,benzyl alcohol, etc.), nitriles (acetonitrile, etc.),N,N-dimethylformamide, dimethyl sulfoxide and the like. These solventmay be used in a mixture thereof in an appropriate ratio.

The reaction temperature is generally about −80° C. to about 80° C.,preferably about −40° C. to about 40° C., and the reaction time isgenerally about 5 min to about 48 hr, preferably about 1 hr to about 24hr.

The catalytic hydrogenation reaction can be carried out in the presenceof a catalyst, under hydrogen atmosphere. Examples of the catalystinclude palladiums such as palladium on carbon, palladium hydroxide oncarbon, palladium oxide and the like; nickels such as Raney-nickelcatalyst and the like; platinums such as platinum oxide, platinum oncarbon and the like; rhodiums such as rhodium on carbon and the like,and the like. The amount thereof to be used is generally about 0.001 toabout 1 mol, preferably about 0.01 to about 0.5 mol, per 1 mol of theimine or iminium ion.

The catalytic hydrogenation reaction is generally carried out in asolvent inert to the reaction. Examples of the solvent include alcohols(methanol, ethanol, propanol, butanol, etc.), hydrocarbons (benzene,toluene, xylene, etc.), halogenated hydrocarbons (dichloromethane,chloroform, etc.), ethers (diethyl ether, 1,4-dioxane, tetrahydrofuran,etc.), esters (ethyl acetate, etc.), amides (N,N-dimethylformamide,etc.), carboxylic acids (acetic acid, etc.), water and mixtures thereof.

The hydrogen pressure for the reaction is generally about 1 to about 50atm, preferably about 1 to about 10 atm. The reaction temperature isgenerally about 0° C. to about 150° C., preferably about 20° C. to about100° C., and the reaction time is generally about 5 min to about 72 hr,preferably about 0.5 hr to about 40 hr.

In this step, the imine or iminium ion, which is an intermediate, canalso be used without isolation for the next reduction reaction toproduce compound (Ie) directly from compound (IIa). In this case, the pHof the reaction mixture is preferably adjusted to about 4 to about 5.

Compound (IIa) used in Method T can be produced according to thefollowing Method U.

[Method U]

wherein each symbol is as defined above.

(Step 1)

This step is a step of reacting compound (VIIa) or a salt thereof with acompound represented by the formula:

(hereinafter to be referred to as compound (CIII)) or a salt thereof inthe presence of a base to produce compound (CIV) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 1 of Method A.

(Step 2)

This step is a step of treating compound (CIV) or a salt thereof withphosphorus oxychloride and zinc(II) chloride to produce compound (CV) ora salt thereof.

The amount of the phosphorus oxychloride to be used is generally about 1to 10 mol equivalent, preferably about 1 to 5 mol equivalent, per 1 molof compound (CIV).

The amount of the zinc(II) chloride to be used is generally about 0.1 to2 mol equivalent, preferably about 0.1 to 1 mol equivalent, per 1 mol ofcompound (CIV).

The above-mentioned reaction is generally carried out in a solvent thatdoes not adversely influence the reaction. Examples of the solventinclude hydrocarbons (benzene, toluene, etc.), ethers (diethyl ether,1,4-dioxane, tetrahydrofuran, etc.), nitriles (acetonitrile, etc.),halogenated hydrocarbons (chloroform, dichloromethane, etc.) and thelike, and they may be mixed as appropriate. The reaction temperature isgenerally about −80 to 150° C., preferably about 0 to 10° C., and thereaction time is generally about 0.5 to 100 hr, preferably 0.5 to 10 hr.

(Step 3)

This step is a step of subjecting compound (CV) or a salt thereof to areduction reaction to produce compound (CVI) or a salt thereof.

This step can be performed in the same manner as in the method describedin the “subjecting the imine or iminium ion to a reduction reaction” inStep 5 of Method T.

(Step 4)

This step is a step of subjecting compound (CVI) or a salt thereof to anamino-protecting reaction to produce compound (CVII) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 2 of Method B.

(Step 5)

This step is a step of subjecting compound (CVII) or a salt thereof tohydrolysis to convert compound (CVII) or a salt thereof to compound(CVIII) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method B.

(Step 6)

This step is a step of reacting compound (CVIII) or a salt thereof withcompound (VI) or a salt thereof in the presence of a condensing agent toproduce compound (CIX) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method A or Step 1 of Method A.

(Step 7)

This step is a step of subjecting compound (CIX) or a salt thereof to adeprotection reaction to produce compound (IIa) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 5 of Method B.

Compound (LVIII) can also be produced according to Method V.

[Method V]

(Step 1)

This step is a step of subjecting compound (CXI)(2,2-dimethyl-1,3-dioxane-4,6-dione) to a dehydration condensation withacetone in the presence of morpholine and acetic acid to producecompound (CXII).

Compound (CXI) may be a commercially available product.

The amount of the morpholine and acetic acid to be used is about 0.01 to1 mol equivalent, preferably about 0.01 to 0.05 mol equivalent, per 1mol of compound (CXI), respectively.

The amount of the acetone to be used is about 1 to 100 mol equivalentper 1 mol of compound (CXI). Acetone may be used as a solvent.

The reaction temperature is generally about 0 to 50° C., preferablyabout 0 to 30° C., and the reaction time is generally about 0.5 to 48hr, preferably 1 to 24 hr.

(Step 2)

This step is a step of converting compound (CX) to Grignard reagent(CXa), and then coupling Grignard reagent (CXa) with compound (CXII) toproduce compound (CXIII).

Compound (CX) may be a commercially available product.

The step of converting compound (CX) to Grignard reagent (CXa) can beperformed by reacting compound (CX) with isopropylmagnesium chloride.

Isopropylmagnesium chloride may be a commercially available product. Theamount thereof to be used is about 1 to 2 mol equivalent, preferablyabout 1 to 1.2 mol equivalent, per 1 mol of compound (CX).

This reaction is generally carried out in a solvent that does notadversely influence the reaction. Examples of the solvent includehydrocarbons (benzene, toluene, etc.), ethers (diethyl ether,1,4-dioxane, tetrahydrofuran, etc.) and the like, and they may be mixedas appropriate.

The reaction temperature is generally about −80 to 30° C., preferablyabout −50 to 0° C., and the reaction time is generally about 0.5 to 2hr, preferably 0.5 to 1 hr.

Grignard reagent (CXa) can be used without isolation for the couplingreaction with compound (CXII).

In the coupling reaction with compound (CXII), the amount of compound(CXII) to be used is about 1 to 2 mol equivalent, preferably about 1 to1.2 mol equivalent, per 1 mol of compound (CXa).

This reaction is generally carried out in a solvent that does notadversely influence the reaction, and the solvent used for theabove-mentioned conversion of compound (CX) to Grignard reagent (CXa)can be used.

The reaction temperature is generally about −80 to 30° C., preferablyabout −50 to 0° C., and the reaction time is generally about 0.5 to 2hr, preferably 0.5 to 1 hr.

(Step 3)

This step is a step of treating compound (CXIII) with hydrochloric acidto produce compound (CXIV) or a salt thereof.

The amount of the hydrochloric acid to be used is about 1 to 50 molequivalent, preferably about 1 to 5 mol equivalent, per 1 mol ofcompound (CXIII).

This reaction is generally carried out in a solvent that does notadversely influence the reaction. Examples of the solvent include ethers(diethyl ether, tetrahydrofuran, 1,4-dioxane, etc.), alcohols (methanol,ethanol, 2-propanol, etc.), nitriles (acetonitrile, butyronitrile,etc.), amides (N,N-dimethylformamide, N,N-dimethylacetamide, etc.),sulfoxides (dimethyl sulfoxide, etc.), water and the like, and they maybe mixed as appropriate.

The reaction temperature is generally about 0 to 150° C., preferablyabout 20 to 100° C., and the reaction time is generally about 0.5 to 48hr, preferably 0.5 to 24 hr.

(Step 4)

This step is a step of treating compound (CXIV) with polyphosphoric acidto produce compound (CXV).

The amount of the polyphosphoric acid to be used is about 1 to 50 molequivalent, preferably about 1 to 5 mol equivalent, per 1 mol ofcompound (CXIV).

The reaction temperature is generally about 20 to 150° C., preferablyabout 50 to 100° C., and the reaction time is generally about 0.5 to 24hr, preferably 0.5 to 10 hr.

(Step 5)

This step is a step of treating compound (CXV) with triethylsilane intrifluoroacetic acid solvent to produce compound (CXVI).

The amount of the triethylsilane to be used is about 1 to 10 molequivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (CXV).

The reaction temperature is generally about −20 to 100° C., preferablyabout 0 to 30° C., and the reaction time is generally about 0.5 to 100hr, preferably 1 to 50 hr.

(Step 6)

This step is a step of subjecting compound (CXVI) to an aminationreaction to produce compound (LVIII).

This step can be performed in the same manner as in the method describedin Step 3 of Method I.

When the object product is obtained in a free form by theabove-mentioned reaction, it may be converted to a salt by aconventional method. When it is obtained as a salt, it can also beconverted to a free form or other salt by a conventional method. Thethus-obtained compound (I) can be isolated and purified from thereaction solution by a known means, for example, phase transfer,concentration, solvent extraction, fractionation, crystallization,recrystallization, chromatography and the like.

When compound (I) contains an isomer such as a tautomer, an opticalisomer, a stereoisomer, a regioisomer, a rotamer and the like, anyisomer and a mixture thereof are also encompassed in the compound of thepresent invention. Furthermore, when compound (I) has an optical isomer,an optical isomer resolved from this compound is also encompassed incompound (I).

The compound (I) may be a crystal. Even if compound (I) is in a singlecrystal form or mixed crystal form, it can be provided as compound (I)of the present invention.

Compound (I) may be a pharmaceutically acceptable co-crystal orco-crystal salt. Here, the co-crystal or co-crystal salt means acrystalline substance consisting of two or more particular substanceswhich are solids at room temperature, each of which has differentphysical properties (e.g., structure, melting point, heat of melting,hygroscopicity, solubility, stability etc.). The cocrystal and cocrystalsalt can be produced by cocrystallization known per se.

The compound (I) may be a solvate (e.g., a hydrate (e.g., monohydrate,dihydrate, etc.)) or a nonsolvate (e.g., non-hydrate, etc.). Any of themcan be provided as compound (I) of the present invention.

Any of the above compounds may be labeled or substituted with an isotope(e.g., ²H, ³H, ¹¹C, ¹⁴C, ¹⁸F, 35S, or ¹²⁵I) and provided as compound (I)of the present invention. Compound (I) labeled or substituted with anisotope can be used, for example, as a tracer (PET tracer) used forpositron emission tomography (PET), and is useful in the field such asmedical diagnosis and the like.

The prodrug of compound (I) means a compound which can be converted intocompound (I) by reaction with an enzyme, gastric acid, or the like underphysiological conditions in the living body. In other words, it means acompound which can be converted into compound (I) by enzymaticoxidation, reduction, hydrolysis or the like, or a compound which can beconverted into compound (I) by hydrolysis with gastric acid or the like.Examples of the prodrug of compound (I) include a compound in whichamino of compound (I) is acylated, alkylated, or phosphorylated (e.g.,the amino of compound (I) is eicosanoylated, alanylated,pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, ortert-butylated); a compound in which hydroxyl of compound (I) isacylated, alkylated, phosphorylated, or borated (e.g., hydroxyl ofcompound (I) is acetylated, palmitoylated, propanoylated, pivaloylated,succinylated, fumarylated, alanylated, ordimethylaminomethylcarbonylated); a compound in which carboxy ofcompound (I) is esterified or amidated (e.g., a compound in whichcarboxy of compound (I) is ethyl esterified, phenyl esterified,carboxymethyl esterified, dimethylaminomethyl esterified,pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified,phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterified, cyclohexyloxycarbonylethyl esterified, or methylamidated).These compounds can be produced from compound (I) by a method known perse. The prodrug of compound (I) may be a compound that converts tocompound (I) under physiological conditions as described in Developmentof Pharmaceutical Products, vol. 7, Molecule Design, 163-198, HirokawaShoten (1990).

Since compound (I) and a prodrug thereof [hereinafter sometimes to beabbreviated as the compound of the present invention] show superiorRORγt inhibitory activity, they are also useful as safe medicamentsbased on such action.

For example, the medicament of the present invention containing thecompound of the present invention can be used for a mammal (e.g., mouse,rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc.) as aprophylactic or therapeutic agent for RORγt associated diseases, Th17cell associated diseases and IL-17A or IL-17F associated diseases, morespecifically, the diseases described in (1)-(4) below.

(1) inflammatory diseases (e.g., rheumatoid arthritis, acutepancreatitis, chronic pancreatitis, asthma, bronchial asthma, adultrespiratory distress syndrome, chronic obstructive pulmonary disease(COPD), inflammatory bone disease, inflammatory pulmonary disease,inflammatory bowel disease, celiac disease, hepatitis, systemicinflammatory response syndrome (SIRS), postoperative or posttraumaticinflammation, pneumonia, nephritis, meningitis, cystitis,pharyngolaryngitis, gastric mucosal injury, spondylitis, arthritis,dermatitis, chronic pneumonia, bronchitis, pulmonary infarction,silicosis, pulmonary sarcoidosis, uveitis etc.),(2) autoimmune diseases (e.g., rheumatoid arthritis, ankylosingspondylitis, psoriasis, multiple sclerosis (MS), polymyositis,dermatomyositis (DM), polyarteritis nodosa (PN), mixed connective tissuedisease (MCTD), Sjogren's syndrome, systemic lupus erythematosus (SLE),scleroderma, profundus lupus erythematosus, chronic thyroiditis, Graves'disease, autoimmune gastritis, type I and type II diabetes, autoimmunehemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopicdermatitis, chronic active hepatitis, myasthenia gravis, inflammatorybowel disease (IBD), ulcerative colitis (UC), Crohn's disease, graftversus host disease, Addison's disease, abnormal immunoresponse,arthritis, dermatitis, radiodermatitis etc.),(3) bone or joint degenerative diseases (e.g., rheumatoid arthritis,osteoporosis, osteoarthritis etc.),(4) neoplastic diseases [e.g., malignant tumor, angiogenesis glaucoma,infantile hemangioma, multiple myeloma, acute myeloblastic leukemia,chronic sarcoma, multiple myeloma, chronic myelogenous leukemia,metastasis melanoma, Kaposi's sacroma, vascular proliferation, cachexia,metastasis of the breast cancer, cancer (e.g., colorectal cancer (e.g.,familial colorectal cancer, hereditary nonpolyposis colorectal cancer,gastrointestinal stromal tumor and the like), lung cancer (e.g.,non-small cell lung cancer, small cell lung cancer, malignantmesothelioma and the like), mesothelioma, pancreatic cancer (e.g.,pancreatic duct cancer and the like), gastric cancer (e.g., papillaryadenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma and thelike), breast cancer (e.g., invasive ductal carcinoma, ductal carcinomain situ, inflammatory breast cancer and the like), ovarian cancer (e.g.,ovarian epithelial carcinoma, extragonadal germ cell tumor, ovarian germcell tumor, ovarian low malignant potential tumor and the like),prostate cancer (e.g., hormone-dependent prostate cancer, non-hormonedependent prostate cancer and the like), liver cancer (e.g., primaryliver cancer, extrahepatic bile duct cancer and the like), thyroidcancer (e.g., medullary thyroid carcinoma and the like), kidney cancer(e.g., renal cell carcinoma, transitional cell carcinoma in kidney andurinary duct and the like), uterine cancer, endometrial cancer, braintumor (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuseastrocytoma, anaplastic astrocytoma and the like), melanoma (melanoma),sarcoma, urinary bladder cancer, hematologic cancer and the likeincluding multiple myeloma, hypophyseal adenoma, glioma, acousticneurinoma, retinoblastoma, head and neck cancer, pharyngeal cancer,laryngeal cancer, cancer of the tongue, thymoma, esophagus cancer,duodenal cancer, colorectal cancer, rectal cancer, hepatoma, pancreaticendocrine tumor, cancer of the bile duct, gallbladder cancer, penilecancer, urinary duct cancer, testis tumor, vulvar cancer, cervix cancer,endometrial cancer, uterus sarcoma, cholionic disease, vaginal cancer,skin cancer, fungoid mycosis, basal cell tumor, soft tissue sarcoma,malignant lymphoma, Hodgkin's disease, myelodysplastic syndrome, acutelymphocytic leukemia, chronic lymphocytic leukemia, adult T cellleukemia, chronic bone marrow proliferative disease, pancreaticendocrine tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma,cancer of unknown primary)

The medicament of the present invention can be preferably used as anagent for the prophylaxis or treatment of psoriasis, inflammatory boweldisease (IBD), ulcerative colitis (UC), Crohn's disease (CD), rheumatoidarthritis, multiple sclerosis, uveitis, asthma, ankylopoieticspondylarthritis, systemic lupus erythematosus (SLE) and the like.

In another embodiment, the medicament of the present invention can bepreferably used as an agent for the prophylaxis or treatment ofautoimmune disease, inflammatory disease, bone or articular disease, orneoplastic disease, particularly preferably psoriasis, inflammatorybowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD),rheumatoid arthritis, multiple sclerosis, uveitis, asthma, ankylopoieticspondylarthritis, systemic lupus erythematosus (SLE), chronicobstructive pulmonary diseases, ovarian cancer, non small cell lungcancer, breast cancer, stomach cancer, head and neck cancer, prostatecancer or endometrial cancer.

Here, the above-mentioned “prophylaxis” of a disease means, for example,administration of a medicament containing the compound of the presentinvention to patients who are expected to have a high risk of the onsetdue to some factor relating to the disease but have not developed thedisease or patients who have developed the disease but do not have asubjective symptom, or administration of a medicament containing thecompound of the present invention to patients who are feared to showrecurrence of the disease after treatment of the disease.

The medicament of the present invention shows superior pharmacokinetics(e.g., a half-life of the drug in plasma), low toxicity (e.g., HERGinhibition, CYP inhibition, CYP induction), and decreased druginteraction. In addition, the medicament of the present invention showsparticularly superior pharmacokinetics in oral administration, andtherefore, it shows superior in vivo activity. The compound of thepresent invention can be directly used as a medicament, or as themedicament of the present invention by producing a pharmaceuticalcomposition by mixing with a pharmaceutically acceptable carrier by ameans known per se and generally used in a production method ofpharmaceutical preparations. The medicament of the present invention canbe orally or parenterally administered safely to mammals (e.g., humans,monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs,sheep and goats).

A medicament containing the compound of the present invention can besafely administered solely or by mixing with a pharmacologicallyacceptable carrier according to a method known per se (e.g., the methoddescribed in the Japanese Pharmacopoeia etc.) as the production methodof a pharmaceutical preparation, and in the form of, for example, tablet(including sugar-coated tablet, film-coated tablet, sublingual tablet,orally disintegrating tablet, buccal and the like), pill, powder,granule, capsule (including soft capsule, microcapsule), troche, syrup,liquid, emulsion, suspension, release control preparation (e.g.,immediate-release preparation, sustained-release preparation,sustained-release microcapsule), aerosol, film (e.g., orallydisintegrating film, oral mucosa-adhesive film), injection (e.g.,subcutaneous injection, intravenous injection, intramuscular injection,intraperitoneal injection), drip infusion, transdermal absorption typepreparation, ointment, lotion, adhesive preparation, suppository (e.g.,rectal suppository, vaginal suppository), pellet, nasal preparation,pulmonary preparation (inhalant), eye drop and the like, orally orparenterally (e.g., intravenous, intramuscular, subcutaneous,intraorgan, intranasal, intradermal, instillation, intracerebral,intrarectal, intravaginal, intraperitoneal and intratumoradministrations, administration to the vicinity of tumor, and directadministration to the lesion).

The content of the compound of the present invention in the medicamentof the present invention is about 0.01 to 100% by weight of the entiremedicament. While the dose varies depending on the subject ofadministration, administration route, disease and the like, for example,for oral administration to an adult inflammatory bowel disease (IBD)patient (body weight about 60 kg), it is about 0.1 mg/kg body weight to30 mg/kg body weight, preferably about 1 mg/kg body weight to 20 mg/kgbody weight as an active ingredient (compound (I)) for one day, which isadministered once to several times, preferably once or two to threetimes.

The pharmaceutically acceptable carrier, which may be used for theproduction of the medicament of the present invention, may beexemplified by various organic or inorganic carrier materials that areconventionally used as preparation materials, for example, excipient,lubricant, binding agent and disintegrant for solid preparations; orsolvent, solubilizing agent, suspending agent, isotonic agent, bufferingagent, soothing agent and the like for liquid preparations. Furthermore,when necessary, ordinary additives such as preservative, antioxidant,colorant, sweetening agent, adsorbing agent, wetting agent and the likecan be also used as appropriate in an appropriate amount.

Examples of the excipient include lactose, white sugar, D-mannitol,starch, corn starch, crystalline cellulose, light anhydrous silicic acidand the like.

Examples of the lubricant include magnesium stearate, calcium stearate,talc, colloidal silica and the like.

Examples of the binding agent include crystalline cellulose, whitesugar, D-mannitol, dextrin, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose,gelatin, methylcellulose, carboxymethylcellulose sodium and the like.

Examples of the disintegrant include starch, carboxymethylcellulose,carboxymethylcellulose calcium, carboxymethylstarch sodium,L-hydroxypropylcellulose and the like.

Examples of the solvent include water for injection, alcohol, propyleneglycol, Macrogol, sesame oil, corn oil, olive oil and the like.

Examples of the solubilizing agent include polyethylene glycol,propylene glycol, D-mannitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate and the like.

Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid,lecithin, benzalkonium chloride, benzetonium chloride, glycerinmonostearate and the like; hydrophilic polymers such as polyvinylalcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like; and the like.

Examples of the isotonic agent include glucose, D-sorbitol, sodiumchloride, glycerin, D-mannitol and the like.

Examples of the buffering agent include buffer solutions such asphosphates, acetates, carbonates, citrates and the like.

Examples of the soothing agent include benzyl alcohol and the like.

Examples of the preservative include parahydroxybenzoates,chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid,sorbic acid and the like.

Examples of the antioxidant include sulfites, ascorbic acid,α-tocopherol and the like.

For the prophylaxis or treatment of various diseases, the compound ofthe present invention can also be used together with other medicaments.In the following, a medicament to be used when the compound of thepresent invention is used together with other drug is referred to as“the combination agent of the present invention”.

For example, when the compound of the present invention is used as anRORγt inhibitor, Th17 cell inhibitor, IL-17A or IL-17F inhibitor, it canbe used in combination with the following drugs.

(1) non-steroidal anti-inflammatory drug (NSAIDs)

(i) Classical NSAIDs

alcofenac, aceclofenac, sulindac, tolmetin, etodolac, fenoprofen,thiaprofenic acid, meclofenamic acid, meloxicam, tenoxicam, lornoxicam,nabumeton, acetaminophen, phenacetin, ethenzamide, sulpyrine,antipyrine, migrenin, aspirin, mefenamic acid, flufenamic acid,diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin,ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen,pranoprofen, floctafenine, piroxicam, epirizole, tiaramidehydrochloride, zaltoprofen, gabexate mesylate, camostat mesylate,ulinastatin, colchicine, probenecid, sulfinpyrazone, benzbromarone,allopurinol, sodium aurothiomalate, hyaluronate sodium, sodiumsalicylate, morphine hydrochloride, salicylic acid, atropine,scopolamine, morphine, pethidine, levorphanol, oxymorphone or a saltthereof and the like.

(ii) cyclooxygenase inhibitor (COX-1 selective inhibitor, COX-2selective inhibitor and the like) salicylic acid derivatives (e.g.,celecoxib, aspirin), etoricoxib, valdecoxib, diclofenac, indomethacin,loxoprofen and the like.(iii) nitric oxide-releasing NSAIDs(2) disease-modifying anti-rheumatic drugs (DMARDs)(i) Gold preparation

auranofin and the like.

(ii) penicillamine

D-penicillamine.

(iii) aminosalicylic acid preparation

sulfasalazine, mesalazine, olsalazine, balsalazide.

(iv) antimalarial drug

chloroquine and the like.

(v) pyrimidine synthesis inhibitor

leflunomide and the like.

(vi) tacrolimus(3) anti-cytokine drug(I) protein drug(i) TNF inhibitor

etanercept, infliximab, adalimumab, certolizumab pegol, golimumab,PASSTNF-α, soluble TNF-α receptor, TNF-α binding protein, anti-TNF-αantibody and the like.

(ii) interleukin-1 inhibitor

anakinra (interleukin-1 receptor antagonist), soluble interleukin-1receptor and the like.

(iii) interleukin-6 inhibitor

tocilizumab (anti-interleukin-6 receptor antibody), anti-interleukin-6antibody and the like.

(iv) interleukin-10 drug

interleukin-10 and the like.

(v) interleukin-12/23 inhibitor

ustekinumab, briakinumab (anti-interleukin-12/23 antibody) and the like.

(vi) B cell activation inhibitor

rituxan, benrista and the like.

(vii) co-stimulatory molecules related protein drug

abatacept and the like.

(II) non-protein drug(i) MAPK inhibitor

BMS-582949 and the like.

(ii) gene modulator

inhibitor of molecule involved in signal transduction, such as NF-κ,NF-κB, IKK-1, IKK-2, AP-1 and the like, and the like.

(iii) cytokine production inhibitor

iguratimod, tetomilast and the like.

(iv) TNF-α converting enzyme inhibitor(v) interleukin-1β converting enzyme inhibitor

belnacasan and the like.

(vi) interleukin-6 antagonist

HMPL-004 and the like.

(vii) interleukin-8 inhibitor

IL-8 antagonist, CXCR1 & CXCR2 antagonist, reparixin and the like.

(viii) chemokine antagonist

CCR9 antagonist (vercirnon (vercirnon sodium), CCX025,N-{4-chloro-2-[(1-oxidepyridin-4-yl)carbonyl]phenyl}-4-(propan-2-yloxy)benzenesulfonamide),MCP-1 antagonist and the like.

(ix) interleukin-2 receptor antagonist

denileukin, diftitox and the like.

(x) therapeutic vaccines

TNF-α vaccine and the like.

(xi) gene therapy drug

gene therapy drugs aiming at promoting the expression of gene having ananti-inflammatory action such as interleukin-4, interleukin-10, solubleinterleukin-1 receptor, soluble TNF-α receptor and the like.

(xii) antisense compound

ISIS 104838 and the like.

(4) integrin inhibitor natalizumab, vedolizumab, AJM300, TRK-170, E-6007and the like.(5) immunomodulator (immunosuppressant)

methotrexate, cyclophosphamide, MX-68, atiprimod dihydrochloride,abatacept, CKD-461, rimexolone, cyclosporine, tacrolimus, gusperimus,azathiopurine, antilymphocyte serum, freeze-dried sulfonated normalimmunoglobulin, erythropoietin, colony stimulating factor, interleukin,interferon and the like.

(6) proteasome inhibitor

velcade and the like.

(7) JAK inhibitor

tofacitinib and the like.

(8) steroid

dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone,triamcinolone acetonide, fluocinonide, fluocinolone acetonide,predonisolone, methylpredonisolone, cortisone acetate, hydrocortisone,fluorometholone, beclomethasone dipropionate, estriol and the like.

(9) angiotensin converting enzyme inhibitor

enalapril, captopril, ramipril, lisinopril, cilazapril, perindopril andthe like.

(10) angiotensin II receptor antagonist

candesartan cilexetil, valsartan, irbesartan, olmesartan, eprosartan andthe like.

(11) diuretic drug

hydrochlorothiazide, spironolactone, furosemide, indapamide,bendrofluazide, cyclopenthiazide and the like.

(12) cardiotonic drug

digoxin, dobutamine and the like.

(13) P receptor antagonist

carvedilol, metoprolol, atenolol and the like.

(14) Ca sensitizer

caldaret hydrate and the like.

(15) Ca channel antagonist

nifedipine, diltiazem, verapamil and the like.

(16) anti-platelet drug, anticoagulator

heparin, aspirin, warfarin and the like.

(17) HMG-CoA reductase inhibitor

atorvastatin, simvastatin and the like.

(18) contraceptive(i) sex hormone or derivatives thereof

gestagen or a derivative thereof (progesterone, 17α-hydroxyprogesterone, medroxyprogesterone, medroxyprogesterone acetate,norethisterone, norethisterone enanthate, norethindrone, norethindroneacetate, norethynodrel, levonorgestrel, norgestrel, ethynodioldiacetate, desogestrel, norgestimate, gestodene, progestin,etonogestrel, drospirenone, dienogest, trimegestone, nestorone,chlormadinone acetate, mifepristone, nomegestrol acetate, tosagestin,TX-525, ethinylestradiol/TX525) or a combination agent of a gestagen ora derivative thereof and an estrogen or a derivative thereof (estradiol,estradiol benzoate, estradiol cypionate, estradiol dipropionate,estradiol enanthate, estradiol hexahydrobenzoate, estradiolphenylpropionate, estradiol undecanoate, estradiol valerate, estrone,ethinylestradiol, mestranol) and the like.

(ii) antiestrogen

ormeloxifene, mifepristone, Org-33628 and the like.

(iii) spermatocide

ushercell and the like.

(19) others(i) T cell inhibitors(ii) inosine monophosphate dehydrogenase (IMPDH) inhibitor

mycophenolate mofetil and the like.

(iii) adhesion molecule inhibitor

alicaforsen sodium, selectin inhibitor, ELAM-1 inhibitor, VCAM-1inhibitor, ICAM-1 inhibitor and the like.

(iv) thalidomide(v) cathepsin inhibitor(vi) matrix metalloprotease (MMPs) inhibitor

V-85546 and the like.

(vii) glucose-6-phosphate dehydrogenase inhibitor(viii) Dihydroorotate dehydrogenase (DHODH) inhibitor(ix) phosphodiesterase IV (PDE IV) inhibitor

roflumilast, apremilast, CG-1088 and the like.

(x) phospholipase A₂ inhibitor(xi) iNOS inhibitor

VAS-203 and the like.

(xii) microtubule stimulating drug

paclitaxel and the like.

(xiii) microtuble inhibitor

reumacon and the like.

(xiv) MHC class II antagonist(xv) prostacyclin agonist iloprost and the like.(xvi) CD4 antagonist

zanolimumab and the like.

(xvii) CD23 antagonist(xviii) LTB4 receptor antagonist

DW-1350 and the like.

(xix) 5-lipoxygenase inhibitor

zileuton and the like.

(xx) cholinesterase inhibitor

galanthamine and the like.

(xxi) tyrosine kinase inhibitor

Tyk2 inhibitor (WO2010/142752) and the like.

(xxii) cathepsin B inhibitor(xxiii) adenosine deaminase inhibitor

pentostatin and the like.

(xxiv) osteogenesis stimulator(xxv) dipeptidylpeptidase inhibitor(xxvi) collagen agonist(xxvii) capsaicin cream

(xxviii) hyaluronic acid derivative synvisc (hylan G-F 20), orthoviscand the like.

(xxix) glucosamine sulfate(xxx) amiprilose(xxxi) CD-20 inhibitor

rituximab, ibritumomab, tositumomab, ofatumumab and the like.

(xxxii) BAFF inhibitor

belimumab, tabalumab, atacicept, blisibimod and the like.

(xxxiii) CD52 inhibitor

alemtuzumab and the like.

Other concomitant drugs besides the above-mentioned include for example,antibacterial agent, antifungal agent, antiprotozoal agent, antibiotic,antitussive and expectorant drug, sedative, anesthetic, antiulcer drug,antiarrhythmic agent, hypotensive diuretic drug, anticoagulant,tranquilizer, antipsychotic, antitumor drug, hypolipidemic drug, musclerelaxant, antiepileptic drug, antidepressant, antiallergic drug, cardiacstimulants, therapeutic drug for arrhythmia, vasodilator,vasoconstrictor, therapeutic drug for diabetes, antinarcotic, vitamin,vitamin derivative, antiasthmatic, therapeutic agent forpollakisuria/anischuria, therapeutic agent for atopic dermatitis,therapeutic agent for allergic rhinitis, hypertensor,endotoxin-antagonist or -antibody, signal transduction inhibitor,inhibitor of inflammatory mediator activity, antibody to inhibitinflammatory mediator activity, inhibitor of anti-inflammatory mediatoractivity, antibody to inhibit anti-inflammatory mediator activity andthe like. Specific examples thereof include the following.

(1) Antibacterial agent(i) sulfa drug

sulfamethizole, sulfisoxazole, sulfamonomethoxine, salazosulfapyridine,silver sulfadiazine and the like.

(ii) quinolone antibacterial agent

nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin,ofloxacin, tosufloxacin tosylate, ciprofloxacin hydrochloride,lomefloxacin hydrochloride, sparfloxacin, fleroxacin and the like.

(iii) antiphthisic

isoniazid, ethambutol (ethambutol hydrochloride), p-aminosalicylic acid(calcium p-aminosalicylate), pyrazinamide, ethionamide, protionamide,rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine and thelike.

(iv) antiacidfast bacterium drug

diaphenylsulfone, rifampicin and the like.

(v) antiviral drug

idoxuridine, acyclovir, vidarabine, gancyclovir and the like.

(vi) anti-HIV agent zidovudine, didanosine, zalcitabine, indinavirsulfate ethanolate, ritonavir and the like.(vii) antispirochetele(viii) antibiotic

tetracycline hydrochloride, ampicillin, piperacillin, gentamicin,dibekacin, kanendomycin, lividomycin, tobramycin, amikacin, fradiomycin,sisomicin, tetracycline, oxytetracycline, rolitetracycline, doxycycline,ampicillin, piperacillin, ticarcillin, cephalothin, cephapirin,cephaloridine, cefaclor, cephalexin, cefroxadine, cefadroxil,cefamandole, cefotoam, cefuroxime, cefotiam, cefotiam hexetil,cefuroxime axetil, cefdinir, cefditoren pivoxil, ceftazidime,cefpiramide, cefsulodin, cefmenoxime, cefpodoxime proxetil, cefpirome,cefozopran, cefepime, cefsulodin, cefmenoxime, cefmetazole, cefminox,cefoxitin, cefbuperazone, latamoxef, flomoxef, cefazolin, cefotaxime,cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin,aztreonam or a salt a salt thereof, griseofulvin, lankacidin-group[Journal of Antibiotics (J. Antibiotics), 38, 877-885(1985)], azolecompound[2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone, fluconazole, itraconazole and the like] and thelike.

(2) antifungal agent(i) polyethylene antibiotic (e.g., amphotericin B, nystatin,

trichomycin)

(ii) griseofulvin, pyrrolnitrin and the like(iii) cytosine metabolism antagonist (e.g., flucytosine)(iv) imidazole derivative (e.g., econazole, clotrimazole,

miconazole nitrate, bifonazole, croconazole)

(v) triazole derivative (e.g., fluconazole, itraconazole)(vi) thiocarbamic acid derivative (e.g., trinaphthol) and the

like.

(3) antiprotozoal agent

metronidazole, tinidazole, diethylcarbamazine citrate, quininehydrochloride, quinine sulfate and the like.

(4) antitussive and expectorant drug

ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate,dihydrocodeine phosphate, isoproterenol hydrochloride, ephedrinehydrochloride, methylephedrine hydrochloride, noscapine hydrochloride,alloclamide, chlophedianol, picoperidamine, cloperastine, protokylol,isoproterenol, salbutamol, terbutaline oxymetebanol, morphinehydrochloride, dextromethorfan hydrobromide, oxycodone hydrochloride,dimemorphan phosphate, tipepidine hibenzate, pentoxyverine citrate,clofedanol hydrochloride, benzonatate, guaifenesin, bromhexinehydrochloride, ambroxol hydrochloride, acetylcysteine, ethyl cysteinehydrochloride, carbocysteine and the like.

(5) sedative

chlorpromazine hydrochloride, atropine sulfate, phenobarbital, barbital,amobarbital, pentobarbital, thiopental sodium, thiamylal sodium,nitrazepam, estazolam, flurazepam, haloxazolam, triazolam,flunitrazepam, bromovalerylurea, chloral hydrate, triclofos sodium andthe like.

(6) anesthetic(6-1) local anesthetic

cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucainehydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride,bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethylaminobenzoate, oxethazaine and the like.

(6-2) general anesthetic(i) inhalation anesthetic (e.g., ether, halothane, nitrous

oxide, isoflurane, enflurane),

(ii) intravenous anesthetic (e.g., ketamine hydrochloride, droperidol,thiopental sodium, thiamylal sodium, pentobarbital) and the like.(7) antiulcer drug

histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine,cimetidine, ranitidine, famotidine, urogastrone, oxethazaine,proglumide, omeprazole, sucralfate, sulpiride, cetraxate, gefarnate,aldioxa, teprenone, prostaglandin and the like.

(8) antiarrhythmic agent(i) sodium channel blocker (e.g., quinidine, procainamide,

disopyramide, ajmaline, lidocaine, mexiletine, phenytoin),

(ii) n-blocker (e.g., propranolol, alprenolol, bufetolol hydrochloride,oxprenolol, atenolol, acebutolol, metoprolol, bisoprolol, pindolol,carteolol, arotinolol hydrochloride),(iii) potassium channel blocker (e.g., amiodarone),(iv) calcium channel blocker (e.g., verapamil, diltiazem) and

the like.

(9) hypotensive diuretic drug

hexamethonium bromide, clonidine hydrochloride, hydrochlorothiazide,trichlormethiazide, furosemide, ethacrynic acid, bumetanide, mefruside,azosemide, spironolactone, potassium canrenoate, triamterene, amiloride,acetazolamide, D-mannitol, isosorbide, aminophylline and the like.

(10) anticoagulant

heparin sodium, sodium citrate, activated protein C, tissue factorpathway inhibitor, antithrombin III, dalteparin sodium, warfarinpotassium, argatroban, gabexate, sodium citrate, ozagrel sodium, ethylicosapentate, beraprost sodium, alprostadil, ticlopidine hydrochloride,pentoxifylline, dipyridamole, tisokinase, urokinase, streptokinase andthe like.

(11) tranquilizer

diazepam, lorazepam, oxazepam, chlordiazepoxide, medazepam, oxazolam,cloxazolam, clotiazepam, bromazepam, etizolam, fludiazepam, hydroxyzineand the like.

(12) antipsychotic

chlorpromazine hydrochloride, prochlorperazine, trifluoperazine,thioridazine hydrochloride, perphenazine maleate, fluphenazineenanthate, prochlorperazine maleate, levomepromazine maleate,promethazine hydrochloride, haloperidol, bromperidol, spiperone,reserpine, clocapramine hydrochloride, sulpiride, zotepine and the like.

(13) antitumor drug

6-O—(N-chloroacetylcarbamoyl)fumagillol, bleomycin, methotrexate,actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarzinostatin,cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil,picibanil, lentinan, levamisole, bestatin, azimexon, glycyrrhizin,doxorubicin hydrochloride, aclarubicin hydrochloride, bleomycinhydrochloride, peplomycin sulfate, vincristine sulfate, vinblastinesulfate, irinotecan hydrochloride, cyclophosphamide, melphalan,busulfan, thiotepa, procarbazine hydrochloride, cisplatin, azathioprine,mercaptopurine, tegafur, carmofur, cytarabine, methyltestosterone,testosterone propionate, testosterone enanthate, mepitiostane,fosfestrol, chlormadinone acetate, leuprorelin acetate, buserelinacetate and the like.

(14) hypolipidemic drug

clofibrate, ethyl2-chloro-3-[4-(2-methyl-2-phenylpropoxy)phenyl]propionate [Chemical andPharmaceutical Bulletin (Chem. Pharm. Bull), 38, 2792-2796 (1990)],pravastatin, simvastatin, probucol, bezafibrate, clinofibrate, nicomol,cholestyramine, dextran sulfate sodium and the like.

(15) muscle relaxant

pridinol, tubocurarine, pancuronium, tolperisone hydrochloride,chlorphenesin carbamate, baclofen, chlormezanone, mephenesin,chlorzoxazone, eperisone, tizanidine and the like.

(16) antiepileptic drug

phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, trimethadione,carbamazepine, phenobarbital, primidone, sulthiame, sodium valproate,clonazepam, diazepam, nitrazepam and the like.

(17) antidepressant

imipramine, clomipramine, noxiptiline, phenelzine, amitriptylinehydrochloride, nortriptyline hydrochloride, amoxapine, mianserinhydrochloride, maprotiline hydrochloride, sulpiride, fluvoxaminemaleate, trazodone hydrochloride and the like.

(18) antiallergic drug

diphenhydramine, chlorpheniramine, tripelennamine, metodilamine,clemizole, diphenylpyraline, methoxyphenamine, sodium cromoglicate,tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine,mequitazine, azelastine hydrochloride, epinastine, ozagrelhydrochloride, pranlukast hydrate, seratrodast and the like.

(19) cardiac stimulants

trans-r-oxocamphor, terephyllol, aminophylline, etilefrine, dopamine,dobutamine, denopamine, aminophylline, vesnarinone, amrinone,pimobendan, ubidecarenone, digitoxin, digoxin, methyldigoxin, lanatosideC, G-strophanthin and the like.

(20) vasodilator

oxyfedrine, diltiazem, tolazoline, hexobendine, bamethan, clonidine,methyldopa, guanabenz and the like.

(21) vasoconstrictor

dopamine, dobutamine denopamine and the like.

(22) hypotensive diuretic

hexamethonium bromide, pentolinium, mecamylamine, ecarazine, clonidine,diltiazem, nifedipine and the like.

(23) therapeutic drug for diabetes

tolbutamide, chlorpropamide, acetohexamide, glibenclamide, tolazamide,acarbose, epalrestat, troglitazone, glucagon, glymidine, glipizide,phenformin, buformin, metformin and the like.

(24) antinarcotic

levallorphan, nalorphine, naloxone or a salt thereof and the like.

(25) liposoluble vitamins(i) vitamin A: vitamin A₁, vitamin A₂ and retinol palmitate(ii) vitamin D: vitamin D₁, D₂, D₃, D₄ and D₅(iii) vitamin E: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol,dl-α-tocopherol nicotinate(iv) vitamin K: vitamin K₁, K₂, K₃ and K₄(v) folic acid (vitamin M) and the like.(26) vitamin derivative

various derivatives of vitamins, for example, vitamin D₃ derivativessuch as 5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol,1-α-hydroxycholecalciferol, calcipotriol and the like, vitamin D₂derivatives such as 5,6-trans-ergocalciferol and the like, and the like.

(27) antiasthmatic

isoprenaline hydrochloride, salbutamol sulfate, procaterolhydrochloride, terbutaline sulfate, trimetoquinol hydrochloride,tulobuterol hydrochloride, orciprenaline sulfate, fenoterolhydrobromide, ephedrine hydrochloride, ipratropium bromide, oxitropiumbromide, flutropium bromide, theophylline, aminophylline, sodiumcromoglicate, tranilast, repirinast, amlexanox, ibudilast, ketotifen,terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride,pranlkast hydrate, seratrodast, dexamethasone, prednisolone,hydrocortisone, hydrocortisone sodium succinate, beclometasonedipropionate, ciclesonide and the like.

(28) therapeutic agent for pollakisuria/anischuria

flavoxate hydrochloride and the like.

(29) therapeutic agent for atopic dermatitis

sodium cromoglicate and the like.

(30) therapeutic agent for allergic rhinitis

sodium cromoglicate, chlorpheniramine maleate, alimemazine tartrate,clemastine fumarate, homochlorcyclizine hydrochloride, fexofenadine,mequitazine, ketotifen fumarate, cetirizine hydrochloride, oxatomide,azelastine, ebastine, epinastine hydrochloride, loratadine and the like.

(31) hypertensor

dopamine, dobutamine, denopamine, digitoxin, digoxin, methyldigoxin,lanatoside C, G-strophanthin and the like.

(32) others

hydroxycam, diacerein, megestrol acetate, nicergoline, prostaglandinsand the like.

For combined use, the administration time of the compound of the presentinvention and the concomitant drug is not restricted, and the compoundof the present invention or the concomitant drug can be administered toan administration subject simultaneously, or may be administered atdifferent times. The dosage of the concomitant drug may be determinedaccording to the dose clinically used, and can be appropriately selecteddepending on an administration subject, administration route, disease,combination and the like.

The administration form of the combined use is not particularly limited,and the compound of the present invention and a concomitant drug onlyneed to be combined on administration. Examples of such administrationmode include the following:

(1) administration of a single preparation obtained by simultaneouslyprocessing the compound of the present invention and the concomitantdrug, (2) simultaneous administration of two kinds of preparations ofthe compound of the present invention and the concomitant drug, whichhave been separately produced, by the same administration route, (3)administration of two kinds of preparations of the compound of thepresent invention and the concomitant drug, which have been separatelyproduced, by the same administration route in a staggered manner, (4)simultaneous administration of two kinds of preparations of the compoundof the present invention and the concomitant drug, which have beenseparately produced, by different administration routes, (5)administration of two kinds of preparations of the compound of thepresent invention and the concomitant drug, which have been separatelyproduced, by different administration routes in a staggered manner(e.g., administration in the order of the compound of the presentinvention and the concomitant drug, or in the reverse order) and thelike.

The mixing ratio of the compound of the present invention and aconcomitant drug in the combination agent of the present invention canbe appropriately selected based on the subject of administration,administration route, disease and the like.

For example, while the content of the compound of the present inventionin the combination agent of the present invention varies depending onthe preparation form, it is generally about 0.01-100 wt %, preferablyabout 0.1-50 wt %, more preferably about 0.5-20 wt %, of the wholepreparation.

The content of the concomitant drug in the combination agent of thepresent invention varies depending on the preparation form, andgenerally about 0.01 to 100% by weight, preferably about 0.1 to 50% byweight, further preferably about 0.5 to 20% by weight, of the entirepreparation.

While the content of the additive such as a carrier and the like in thecombination agent of the present invention varies depending on the formof a preparation, it is generally about 1 to 99.99% by weight,preferably about 10 to 90% by weight, based on the preparation.

When the compound of the present invention and the concomitant drug areseparately prepared, the same content may be adopted.

The dose varies depending on the kind of the compound of the presentinvention, administration route, symptom, age of patients and the like.For example, for oral administration to patients (body weight about 60kg) with inflammatory bowel disease (IBD), about 0.1 mg/kg bodyweight—about 30 mg/kg body weight, preferably about 1 mg/kg bodyweight—20 mg/kg body weight, of compound (I) can be administered once toseveral portions per day.

The dose of the medicament of the present invention as asustained-release preparation varies depending on the kind and contentof compound (I), dosage form, period of sustained drug release, subjectanimal of administration (e.g., mammals such as mouse, rat, hamster,guinea pig, rabbit, cat, dog, bovine, horse, swine, sheep, monkey, humanand the like), and administration object. For example, for applicationby parenteral administration, about 0.1 to about 100 mg of compound (I)needs to be released from the administered preparation per 1 week.

Any amount of the concomitant drug can be adopted as long as the sideeffects do not cause a problem. The daily dosage in terms of theconcomitant drug varies depending on the severity, age, sex, bodyweight, sensitivity difference of the subject, administration period,interval, and nature, pharmacology, kind of the pharmaceuticalpreparation, kind of effective ingredient, and the like, and notparticularly restricted, and the amount of a drug is, in the case oforal administration for example, generally about 0.001 to 2000 mg,preferably about 0.01 to 500 mg, further preferably about 0.1 to 100 mg,per 1 kg of a mammal and this is generally administered once to 4-timesdivided in a day.

When the combination agent of the present invention is administered, thecompound of the present invention and the concomitant drug can beadministered simultaneously, or may be administered in a staggeredmanner. When administered at a time interval, the interval variesdepending on the effective ingredient, dosage form and administrationmethod, and, for example, when the concomitant drug is administeredfirst, a method in which the compound of the present invention isadministered within time range of from 1 minute to 3 days, preferablyfrom 10 minutes to 1 day, more preferably from 15 minutes to 1 hour,after administration of the concomitant drug is an example. When thecompound of the present invention is administered first, a method inwhich the concomitant drug is administered within time range of from 1minute to 1 day, preferably from 10 minutes to 6 hours, more preferablyfrom 15 minutes to 1 hour after administration of the compound of thepresent invention is an example.

EXAMPLES

The present invention is explained in more detail in the following byreferring to Examples, Formulation Examples and Experimental Examples,which are not to be construed as limitative and may be modified withoutdeparting from the scope of the invention.

Unless particularly specified, the elution in column chromatography inthe Examples was performed under observation by TLC (Thin LayerChromatography). For TLC observation, 60F254 manufactured by Merck wasused as a TLC plate, and the solvent used as an elution solvent forcolumn chromatography was used as a developing solvent. For detection, aUV detector was adopted. In silica gel column chromatography, NH meansuse of aminopropylsilane-bonded silica gel, and Diol means use of3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel. In preparativeHPLC (high performance liquid chromatography), C18 means use ofoctadecyl-bonded silica gel. The ratios of elution solvents are volumemixing ratios, unless otherwise specified. The room temperaturegenerally means a temperature about 10° C. to 35° C. For dryingextracts, sodium sulfate or magnesium sulfate was used.

In the chemical structure formulas described in Examples, the wavy linebonded to the asymmetric carbon

means one stereochemical structure which is not determined, and thesolid line

means a mixture of two stereochemical structure.

The abbreviations in the present specification or the Examples mean asfollows.

LC: liquid chromatographyMS: mass analysis spectrumAPI: atmospheric pressure ionization methodM: molecular weight of the compoundNMR: nuclear magnetic resonance spectrumHz: hertzJ: coupling constantm: multipletq: quartett: tripletd: doublets: singletdt: double tripletsxt: sextetbrs: broad singletquant.: quantitativeADDP: 1,1′-(azodicarbonyl)dipiperidineAIBN: 2,2′-azobis(isobutyronitrile)BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthylBoc: tert-butyloxycarbonyl groupBoc₂O: di-tert-butyl dicarbonateCDI: carbonyldiimidazoleCOMU:1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethylamino-morpholino)]carbeniumhexafluorophosphateCPME: cyclopentyl methyl etherDBU: 1,8-diazabicyclo[5.4.0]undec-7-eneDEAD: diethyl azodicarboxylateDIAD: diisopropyl azodicarboxylateDIBAL-H: diisobutylaluminium hydrideDIEA: diisopropylethylamine

DMA: N,N-dimethylacetamide

DMAP: 4-dimethylaminopyridineDME: dimethoxyethane

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxideDPPA: diphenylphosphoryl azideEt₂O: diethyl etherEtOH: ethanolHATU: 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphorateHMDS: 1,1,1,2,2,2-hexamethyldisilaneHOBt: 1H-benzo[d][1,2,3]triazol-1-ol hydrateIPE: diisopropyl etherMeOH: methanolM: mol concentrationN: normal concentrationNaHMDS: sodium bis(trimethylsilyl)amide

NBS: N-bromosuccinimide

n-BuLi: 1.6M n-butyllithium/hexane solutionNMP: N-methyl-2-pyrrolidonePd(PPh₃)₄: tetrakis(triphenylphosphine)palladium(0)Pd₂(dba)₃: tris(dibenzylideneacetone)dipalladium(0)PdCl₂(dppf): 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complexPPA: polyphosphoric acidPPh₃: triphenylphosphinet-: tert-T3P: 1.6M2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide/ethylacetate solution, or DMF solutionTEA: triethylamineTFA: trifluoroacetic acidTHF: tetrahydrofuranTMSCl: trimethylsilyl chloride or trimethylsilane chlorideWSC: N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochlorideXANTPHOS: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Example 12-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-N-(4-(trimethylsilyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

To a 0.5M (4-(bis(trimethylsilyl)amino)phenyl)magnesium chloride/THFsolution (100 mL, 50.00 mmol) was added trimethylsilyl chloride (7.03mL, 55.00 mmol), and the mixture was stirred at room temperature for 30min. To the reaction mixture was added 0.1N hydrochloric acid withcooling, and the mixture was stirred for 10 min. Then, aqueous sodiumhydrogen carbonate solution and ethyl acetate were added thereto, andthe organic layer was separated. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 5→30% ethyl acetate/hexane) togive 4-(trimethylsilyl)aniline (6.51 g, 39.4 mmol, 79%) as a pale yellowoil.

¹H NMR (300 MHz, DMSO-dr): δ 0.09-0.19 (9H, m), 5.14 (2H, s), 6.49-6.60(2H, m), 7.09-7.19 (2H, m).

(Step 2)

A solution of 3-(2-aminoethyl)phenol hydrochloride (4.60 g, 26.49 mmol)and 47% ethyl glyoxylate (6.15 mL, 29.14 mmol) in a mixed solvent oftoluene/EtOH (50 mL) was heated under reflux for 18 hr. The reactionmixture was concentrated under reduced pressure. The precipitate wascollected by filtration, and washed with ethyl acetate/diethyl ether togive ethyl 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylatehydrochloride (6.15 g, 23.86 mmol, 90%) as white crystals.

¹H NMR (300 MHz, DMSO-d): δ 1.25 (3H, t, J=7.0 Hz), 2.94 (2H, t, J=6.2Hz), 3.35 (1H, brs), 3.38-3.52 (2H, m), 4.26 (2H, q, J=7.1 Hz), 5.27(1H, s), 6.64 (1H, d, J=2.3 Hz), 6.73 (1H, dd, J=8.7, 2.6 Hz), 7.21 (1H,d, J=8.7 Hz), 9.77 (1H, s), 9.99 (1H, brs) (The exchangeable 1H was notobserved)

(Step 3)

Boc₂O (5.47 g, 25.06 mmol) was added to a solution of ethyl6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylate hydrochloride(6.15 g, 23.86 mmol) and TEA (3.33 mL, 23.86 mmol) in a mixed solvent ofTHF (65 mL) and water (25 mL) at room temperature, and the mixture wasstirred for 2 hr. To the reaction mixture was added water, and themixture was extracted three times with ethyl acetate. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 5→30% ethylacetate/hexane) to give 1-ethyl 2-tert-butyl6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (7.85 g, 24.43mmol, quant.) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.19-1.29 (3H, m), 1.45-1.52 (9H, m),2.72-2.96 (2H, m), 3.65-3.83 (2H, m), 4.08-4.19 (2H, m), 5.16-5.50 (2H,m), 6.63 (1H, s), 6.67-6.73 (1H, m), 7.31-7.37 (1H, m).

(Step 4)

Iodomethane (3.04 mL, 48.85 mmol) was added to a solution of 1-ethyl2-tert-butyl 6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate(7.85 g, 24.43 mmol) and cesium carbonate (10.35 g, 31.75 mmol) in DMF(50 mL) at room temperature, and the mixture was stirred for 2.5 hr. Tothe reaction mixture was added water, and the mixture was extractedthree times with ethyl acetate. The organic layer was washed with 0.1%aqueous sodium thiosulfate solution and brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure to give1-ethyl 2-tert-butyl6-methoxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (8.23 g, 24.54mmol, 100%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.20-1.29 (3H, m), 1.46-1.51 (9H, m),2.75-2.99 (2H, m), 3.69-3.81 (5H, m), 4.08-4.19 (2H, m), 5.33-5.51 (1H,m), 6.68 (1H, s), 6.77 (1H, dd, J=8.3, 2.6 Hz), 7.36-7.43 (1H, m).

(Step 5)

2N Aqueous lithium hydroxide solution (73.6 mL, 147.23 mmol) was addedto a solution of 1-ethyl 2-tert-butyl6-methoxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (8.23 g, 24.54mmol) in a mixed solvent of EtOH (35 mL) and THF (35 mL) at roomtemperature, and the mixture was stirred for 2 hr. To the reactionmixture was added water, 2N hydrochloric acid was added thereto untilthe pH of the mixture became 3, and the mixture was extracted threetimes with ethyl acetate. The organic layer was washed with brine, anddried over magnesium sulfate, and the solvent was evaporated underreduced pressure to give2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (7.59 g, 24.70 mmol, quant.) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.41-1.52 (9H, m), 2.72-3.00 (2H, m),3.56-3.67 (1H, m), 3.71-3.87 (4H, m), 5.33-5.53 (1H, m), 6.68 (1H, d,J=2.3 Hz), 6.77 (1H, dd, J=8.7, 2.3 Hz), 7.37 (1H, d, J=8.7 Hz) (Theexchangeable 1H was not observed).

(Step 6)

HATU (2.281 g, 6.00 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (1.537 g, 5 mmol), 4-(trimethylsilyl)aniline (0.827 g, 5.00 mmol)and DIEA (1.742 mL, 10.00 mmol) in DMF (20 mL) at room temperature, andthe mixture was stirred at room temperature for 15 hr. To the reactionmixture was added aqueous sodium hydrogen carbonate solution, and themixture was extracted three times with ethyl acetate. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The precipitate was washed withIPE/hexane to give tert-butyl6-methoxy-1-((4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.86 g, 4.09 mmol, 82%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 0.23 (9H, s), 1.52 (9H, s), 2.79-3.02 (3H,m), 3.51-3.87 (5H, m), 5.62 (1H, brs), 6.72 (1H, d, J=2.3 Hz), 6.81 (1H,dd, J=8.3, 2.6 Hz), 7.41-7.54 (4H, m), 8.82 (1H, brs).

(Step 7)

Cooled TFA (25 mL) was added to tert-butyl6-methoxy-1-((4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.86 g, 4.09 mmol), and the mixture was stirred at room temperature for5 min. The reaction mixture was added to ice and aqueous sodium hydrogencarbonate solution, and potassium carbonate was added thereto until thepH of the mixture became 8. Then, the mixture was extracted three timeswith a mixed solvent of ethyl acetate/THF (3:1). The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The precipitate was washed withIPE/hexane to give6-methoxy-N-(4-(trimethylsilyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(1.12 g, 3.16 mmol, 77%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 0.23 (9H, s), 1.83 (1H, brs), 2.70-2.81 (1H,m), 2.84-2.96 (1H, m), 3.14 (2H, t, J=5.7 Hz), 3.78 (3H, s), 4.63 (1H,s), 6.64 (1H, s), 6.78 (1H, dd, J=8.7, 2.3 Hz), 7.44 (2H, d), 7.51-7.59(3H, m), 9.33 (1H, brs).

(Step 8)

HATU (319 mg, 0.84 mmol) was added to a solution of6-methoxy-N-(4-(trimethylsilyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(248 mg, 0.70 mmol), 3-hydroxy-1,2-oxazole-5-carboxylic acid (95 mg,0.73 mmol) and DIEA (244 μL, 1.40 mmol) in DMF (3.5 mL) at roomtemperature, and the mixture was stirred at room temperature for 15 hr.To the reaction mixture was added water, and the mixture was extractedthree times with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 30→100% ethyl acetate/hexane), and theprecipitate was washed with IPE/hexane to give the title compound (109.1mg, 0.234 mmol, 33.5%) as white crystals.

MS(API): Calculated 465.6. Found 466.1 (M+H).

¹H NMR (300 MHz, CDCl₃): δ 0.23 (9H, s), 1.25-1.30 (1H, m), 3.04-3.12(2H, m), 3.82 (3H, s), 3.85-3.97 (1H, m), 4.08-4.18 (1H, m), 6.00 (1H,s), 6.54 (1H, s), 6.77 (1H, d, J=2.6 Hz), 6.85 (1H, dd, J=8.7, 2.6 Hz),7.17 (1H, d, J=8.7 Hz), 7.45 (2H, d), 7.52 (2H, d), 8.68 (1H, s).

Example 26-methoxy-2-((6-oxo-1,6-dihydropyridin-3-yl)carbonyl)-N-(4-(trimethylsilyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

HATU (319 mg, 0.84 mmol) was added to a solution of6-methoxy-N-(4-(trimethylsilyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(248 mg, 0.70 mmol), 6-oxo-1,6-dihydropyridine-3-carboxylic acid (102mg, 0.73 mmol) and DIEA (244 μL, 1.40 mmol) in DMF (3.5 mL) at roomtemperature, and the mixture was stirred at room temperature for 15 hr.To the reaction mixture was added water, and the mixture was extractedthree times with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→8% MeOH/ethyl acetate), and theprecipitate was washed with ethyl acetate/IPE to give the title compound(58.2 mg, 0.122 mmol, 17.49%) as white crystals.

MS(API): Calculated 475.6. Found 474.2 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ 0.21 (9H, s), 2.83-2.94 (1H, m), 3.03-3.15(1H, m), 3.70-3.81 (4H, m), 3.98-4.08 (1H, m), 5.63 (1H, s), 6.36 (1H,d, J=9.4 Hz), 6.81-6.86 (2H, m), 7.43 (2H, d, J=8.3 Hz), 7.49-7.60 (4H,m), 7.67 (1H, brs), 10.45 (1H, brs), 11.89 (1H, brs).

Example 3N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

A solution of 1-chloro-2-fluoro-4-nitrobenzene (2.63 g, 15 mmol), HMDS(8.12 g, 55.50 mmol) and Pd(PPh₃)₄ (0.433 g, 0.38 mmol) in xylene (6.5mL) was stirred under microwave irradiation at 200° C. for 1 hr. To thereaction mixture was added ethyl acetate (about 150 mL), and theinsoluble substance was removed by filtration. The filtrate wasconcentrated under reduced pressure, and the obtained residue waspurified by NH-silica gel column chromatography (solvent gradient; 2→5%ethyl acetate/hexane) to give (2-fluoro-4-nitrophenyl)trimethylsilane(3.22 g, 15.10 mmol, 101%) as a yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 0.36 (9H, d, J=1.1 Hz), 7.57 (1H, dd, J=8.1,5.5 Hz), 7.82 (1H, dd, J=8.1, 2.1 Hz), 7.99 (1H, dd, J=8.1, 2.1 Hz).

(Step 2)

A solution of (2-fluoro-4-nitrophenyl)trimethylsilane (3.22 g, 15.10mmol) and 10% palladium-carbon (1.0 g, 0.47 mmol, 50% wet) in MeOH (65mL) was stirred at room temperature for 3.5 hr under hydrogen atmosphere(1 atm). The catalyst was removed by filtration, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 2→15% MeOH/ethylacetate) to give 3-fluoro-4-(trimethylsilyl)aniline (1.89 g, 10.31 mmol,68.3%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 0.26 (9H, d, J=0.8 Hz), 3.79 (2H, brs), 6.31(1H, dd, J=10.6, 2.3 Hz), 6.44 (1H, dd, J=7.9, 1.9 Hz), 7.13 (1H, dd,J=7.9, 6.8 Hz).

(Step 3)

T3P (4.46 mL, 7.50 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (1.537 g, 5 mmol), 3-fluoro-4-(trimethylsilyl)aniline (0.916 g,5.00 mmol), DIEA (4.35 mL, 25.00 mmol) and DMAP (0.672 g, 5.50 mmol) inethyl acetate (35 mL), and the mixture was stirred at 70° C. for 18 hr.To the reaction mixture was added water, and the mixture was extractedthree times with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 2→20% ethyl acetate/hexane), and theprecipitate was washed with IPE/hexane to give tert-butyl1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.85 g, 3.91 mmol, 78%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 0.27 (9H, s), 1.52 (9H, s), 2.80-2.96 (2H,m), 3.55-3.76 (2H, m), 3.80 (3H, s), 5.61 (1H, brs), 6.72 (1H, d, J=2.3Hz), 6.81 (1H, dd, J=8.3, 2.6 Hz), 7.09 (1H, d, J=7.9 Hz), 7.24-7.30(2H, m), 7.39 (1H, dd, J=10.6, 1.9 Hz), 9.00 (1H, brs).

(Step 4)

Cooled TFA (25 mL) was added to tert-butyl1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.85 g, 3.91 mmol), and the mixture was stirred at room temperature for2 min. The reaction mixture was added to ice and aqueous sodium hydrogencarbonate solution, and potassium carbonate was added thereto until thepH of the mixture became 8. Then, the mixture was extracted three timeswith ethyl acetate. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The precipitate was washed with ethyl acetate. The filtratewas concentrated, the obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→5% MeOH/ethyl acetate), and theprecipitate was combined with the previously-obtained precipitate, andwashed with IPE/hexane to giveN-(3-fluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(919 mg, 2.467 mmol, 63.0%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 0.27 (9H, d, J=1.1 Hz), 2.23 (1H, brs),2.69-2.80 (1H, m), 2.84-2.94 (1H, m), 3.14 (2H, t, J=5.9 Hz), 3.78 (3H,s), 4.63 (1H, s), 6.64 (1H, d, J=2.6 Hz), 6.78 (1H, dd, J=8.7, 2.6 Hz),7.17 (1H, dd), 7.24-7.30 (1H, m), 7.45 (1H, dd, J=10.6, 1.9 Hz), 7.53(1H, d, J=8.7 Hz), 9.45 (1H, s).

(Step 5)

HATU (561 mg, 1.48 mmol) was added to a solution ofN-(3-fluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(458 mg, 1.23 mmol), 3-hydroxy-1,2-oxazole-5-carboxylic acid (167 mg,1.29 mmol) and DIEA (428 μL, 2.46 mmol) in DMF (6 mL) at roomtemperature, and the mixture was stirred at room temperature for 15 hr.To the reaction mixture was added water, and the mixture was extractedthree times with a mixed solvent of ethyl acetate/THF (3:1). The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 30→100%ethyl acetate/hexane), and the precipitate was washed with IPE/hexane togive the title compound (272.4 mg, 0.563 mmol, 45.8%) as white crystals.

MS(API): Calculated 483.6. Found 484.2 (M+H).

¹H NMR (300 MHz, CDCl₃): δ 0.27 (9H, s), 1.72 (1H, brs), 3.08 (2H, t,J=5.7 Hz), 3.82 (3H, s), 3.87-3.97 (1H, m), 4.09-4.19 (1H, m), 5.98 (1H,s), 6.56 (1H, s), 6.77 (1H, d, J=2.3 Hz), 6.85 (1H, dd, J=8.5, 2.5 Hz),7.12-7.20 (2H, m), 7.25-7.31 (1H, m), 7.39 (1H, dd, J=10.6, 1.5 Hz),8.85 (1H, s).

Example 4N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-methoxy-2-((6-oxo-1,6-dihydropyridin-3-yl)carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

HATU (561 mg, 1.48 mmol) was added to a solution ofN-(3-fluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(458 mg, 1.23 mmol), 6-oxo-1,6-dihydropyridine-3-carboxylic acid (180mg, 1.29 mmol) and DIEA (428 μL, 2.46 mmol) in DMF (6 mL) at roomtemperature, and the mixture was stirred for 15 hr. To the reactionmixture was added water, and the mixture was extracted three times witha mixed solvent of ethyl acetate/THF (3:1). The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure to give a precipitate. The precipitatewas washed with IPE/hexane, and recrystallized from MeOH/ethyl acetateto give the title compound (394.6 mg, 0.799 mmol, 65.0%) as whitecrystals.

MS(API): Calculated 493.6. Found 492.2 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ 0.25 (9H, s), 2.83-2.94 (1H, m), 3.03-3.15(1H, m), 3.66-3.81 (4H, m), 3.98-4.08 (1H, m), 5.60 (1H, s), 6.36 (1H,d, J=9.8 Hz), 6.81-6.87 (2H, m), 7.28-7.39 (2H, m), 7.44-7.53 (2H, m),7.58 (1H, d, J=9.1 Hz), 7.68 (1H, brs), 10.69 (1H, brs), 11.91 (1H,brs).

Example 54-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-8-methoxy-N-(4-(trimethylsilyl)phenyl)-2,3,4,5-tetrahydro-,4-benzoxazepine-5-carboxamide (Step 1)

Boc₂O (16.67 g, 76.39 mmol) was added to a solution of2-(benzylamino)ethanol (11.00 g, 72.75 mmol) in THF (220 mL) at roomtemperature, and the mixture was stirred at room temperature for 16 hr.The reaction mixture was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent gradient; 10→60-ethyl acetate/hexane) to give tert-butylbenzyl(2-hydroxyethyl)carbamate (18.26 g, 72.7 mmol, 100%) as acolorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.47 (9H, s), 3.03 (1H, brs), 3.40 (2H, brs),3.65-3.75 (2H, m), 4.48 (2H, brs), 7.21-7.37 (5H, m).

(Step 2)

1.9 M DIAD toluene solution (47.8 mL, 90.87 mmol) was added to asolution of tert-butyl benzyl(2-hydroxyethyl)carbamate (18.27 g, 72.69mmol), 3-methoxyphenol (7.52 g, 60.58 mmol) and triphenylphosphine(23.83 g, 90.87 mmol) in THF (250 mL) at 0° C. under argon gasatmosphere, and the mixture was stirred at room temperature for 3 days.To the reaction mixture was added water, and the mixture was extractedthree times with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 2→15% ethyl acetate/hexane) to givetert-butyl benzyl(2-(3-methoxyphenoxy)ethyl)carbamate (8.83 g, 24.70mmol, 40.8%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.41-1.53 (9H, m), 3.47-3.63 (2H, m), 3.78(3H, s), 3.97-4.14 (2H, m), 4.57 (2H, brs), 6.39-6.53 (3H, m), 7.16 (1H,t, J=8.1 Hz), 7.22-7.36 (5H, m).

(Step 3)

Cooled TFA (30 mL) was added to tert-butylbenzyl(2-(3-methoxyphenoxy)ethyl)carbamate (8.83 g, 24.70 mmol), and themixture was stirred at room temperature for 15 min. The reaction mixturewas added to ice and aqueous sodium hydrogen carbonate solution, and 8Naqueous sodium hydroxide solution and potassium carbonate were addedthereto until the pH of the mixture became 8. Then, the mixture wasextracted three times with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure to giveN-benzyl-2-(3-methoxyphenoxy)ethanamine (6.34 g, 24.64 mmol, 100%) as acolorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.71 (1H, brs), 3.02 (2H, t, J=5.3 Hz), 3.78(3H, s), 3.88 (2H, s), 4.08 (2H, t, J=5.3 Hz), 6.46-6.53 (3H, m), 7.17(1H, t, J=8.1 Hz), 7.27-7.38 (5H, m).

(Step 4)

A solution of methyl 2-methoxyacetate (2.82 g, 27.10 mmol), NBS (5.04 g,28.33 mmol) and AIBN (0.081 g, 0.49 mmol) in trifluoromethylbenzene (50mL) was stirred at 80° C. for 5 hr. The reaction solution was cooled,and the precipitate was removed by filtration. The filtrate wasconcentrated under reduced pressure to give an oil. The obtained oil wasadded to a solution of N-benzyl-2-(3-methoxyphenoxy)ethanamine (6.34 g,24.64 mmol) and DIEA (5.15 mL, 29.57 mmol) in THF (60 mL) at roomtemperature, and the mixture was stirred at room temperature for 1 hr.The reaction mixture was added to aqueous sodium hydrogen carbonatesolution, and the mixture was extracted three times with ethyl acetate.The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by NH-silica gel column chromatography(solvent gradient; 2→20% ethyl acetate/hexane) to give methyl2-(benzyl(2-(3-methoxyphenoxy)ethyl)amino)-2-methoxyacetate (6.72 g,18.70 mmol, 76%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 3.12 (2H, td, J=5.9, 1.5 Hz), 3.39 (3H, s),3.77 (3H, s), 3.77 (3H, s), 3.87-4.08 (4H, m), 4.48 (1H, s), 6.38-6.53(3H, m), 7.15 (1H, t, J=8.1 Hz), 7.24-7.39 (5H, m).

(Step 5)

Chlorotrimethylsilane (2.85 mL, 22.44 mmol) was added to a solution ofmethyl 2-(benzyl(2-(3-methoxyphenoxy)ethyl)amino)-2-methoxyacetate (6.72g, 18.70 mmol) in acetonitrile (75 mL) at 0° C., and the mixture wasstirred at room temperature for 1 hr. The reaction mixture was added toaqueous sodium hydrogen carbonate solution, and the mixture wasextracted three times with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 3→80% ethylacetate/hexane) to give methyl4-benzyl-8-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylate(3.65 g, 11.15 mmol, 59.6%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 2.97 (1H, ddd), 3.56 (1H, ddd, J=14.5, 8.7,2.5 Hz), 3.67-3.82 (7H, m), 3.95 (1H, d, J=13.6 Hz), 3.98-4.06 (1H, m),4.12-4.20 (1H, m), 4.49 (1H, s), 6.58 (1H, dd), 6.61 (1H, d), 6.87 (1H,d, J=8.3 Hz), 7.23-7.38 (5H, m)

(Step 6)

A solution of methyl4-benzyl-8-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylate(3.65 g, 11.15 mmol) and 10% palladium-carbon (1.2 g, 0.56 mmol, 50%wet) in MeOH (75 mL) was stirred at room temperature for 3 hr underhydrogen atmosphere (1 atm). The catalyst was removed by filtration, andthe filtrate was concentrated under reduced pressure to give methyl8-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylate (2.54g, 10.71 mmol, 96%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 2.13 (1H, brs), 3.16 (1H, ddd), 3.35 (1H,ddd), 3.78 (3H, s), 3.78 (3H, s), 3.99 (1H, ddd), 4.05-4.12 (1H, m),4.70 (1H, s), 6.59 (1H, dd), 6.62 (1H, d), 6.95 (1H, d, J=8.3 Hz).

(Step 7)

HATU (2.442 g, 6.42 mmol) was added to a solution of methyl8-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylate (1.27g, 5.35 mmol), 3-hydroxy-1,2-oxazole-5-carboxylic acid (0.725 g, 5.62mmol) and DIEA (1.865 mL, 10.71 mmol) in DMF (25 mL) at roomtemperature, and the mixture was stirred at room temperature for 15 hr.To the reaction mixture was added water, and the mixture was extractedthree times with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 50→100% ethyl acetate/hexane) to givemethyl4-(3-hydroxy-1,2-oxazole-5-carbonyl)-8-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylate(1.80 g, 5.17 mmol, 97%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.35 (1H, s), 3.71-3.77 (3H, m), 3.79-3.83(3H, m), 3.96-4.23 (3H, m), 4.38-4.47 (1H, m), 5.75-6.24 (1H, m),6.46-6.50 (1H, m), 6.60 (1H, d, J=2.6 Hz), 6.67 (1H, dd, J=8.3, 2.6 Hz),7.07-7.29 (1H, m).

(Step 8)

2N Aqueous lithium hydroxide solution (10.28 mL, 20.56 mmol) was addedto a solution of methyl4-(3-hydroxy-1,2-oxazole-5-carbonyl)-8-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylate(1.79 g, 5.14 mmol) in a mixed solvent of MeOH (7.5 mL) and THF (7.5 mL)at room temperature, and the mixture was stirred at room temperature for1.5 hr. To the reaction mixture was added water, 2N hydrochloric acidwas added thereto until the pH of the mixture became 2, and the mixturewas extracted three times with a mixed solvent of ethyl acetate/THF. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The precipitatewas washed with IPE/hexane to give4-(3-hydroxy-1,2-oxazole-5-carbonyl)-8-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylicacid (1.07 g, 3.20 mmol, 62.3%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 3.74 (3H, s), 3.88-4.18 (3H, m), 4.26-4.35(1H, m), 5.73-6.14 (1H, m), 6.33-6.53 (1H, m), 6.56 (1H, d, J=2.3 Hz),6.66 (1H, dd, J=8.3, 2.6 Hz), 7.18-7.37 (1H, m), 11.77 (1H, brs), 13.23(1H, brs).

(Step 9)

HATU (274 mg, 0.72 mmol) was added to a solution of4-(3-hydroxy-1,2-oxazole-5-carbonyl)-8-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylicacid (201 mg, 0.60 mmol), 4-(trimethylsilyl)aniline (104 mg, 0.63 mmol)and DIEA (209 μL, 1.20 mmol) in DMF (3 mL) at room temperature, and themixture was stirred at room temperature for 15 hr. To the reactionmixture was added water, and the mixture was extracted three times witha mixed solvent of ethyl acetate/THF. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 30→100% ethyl acetate/hexane),and the precipitate was washed with IPE/hexane to give the titlecompound (81.7 mg, 0.170 mmol, 28.2%) as pale yellow crystals.

MS(API): Calculated 481.6. Found 482.1 (M+H).

¹H NMR (300 MHz, CDCl₃): δ 0.22 (9H, s), 1.83 (1H, brs), 3.73-4.24 (6H,m), 4.34-4.60 (1H, m), 5.87-6.41 (1H, m), 6.49 (1H, s), 6.68-6.77 (2H,m), 7.15-7.34 (2H, m), 7.36 (2H, d, J=8.3 Hz), 7.43 (2H, d).

Example 6 8-methoxy-4-((6-oxo-1,6-dihydropyridin-3-yl)carbonyl)-N-(4-(trimethylsilyl)phenyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-carboxamide

The title compound was obtained using methyl8-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylate and6-oxo-1,6-dihydropyridine-3-carboxylic acid, by the reaction andpurification in the same manner as in Steps 7 to 9 of Example 5.

MS(API): Calculated 491.6. Found 490.2 (M−H).

¹H NMR (300 MHz, CDCl₃): δ 0.23 (9H, s), 1.60 (1H, brs), 3.84 (3H, s),3.87-4.02 (3H, m), 4.33-4.43 (2H, m), 6.59 (1H, d, J=9.4 Hz), 6.69 (1H,s), 6.73 (1H, dd), 7.26 (1H, s), 7.35 (2H, d), 7.43 (2H, d), 7.64 (1H,dd, J=9.4, 2.3 Hz), 7.74 (1H, d, J=1.5 Hz), 12.15 (1H, brs).

Example 7(1R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

N-(3-Fluoro-4-(trimethylsilyl)phenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (220mg) was resolved by chiral column chromatography. The fraction having ashorter retention time was concentrated to give the title compound(105.5 mg, >99% ee) as a white solid.

MS(API): Calculated 483.6. Found 484.2 (M+H).

purification condition by chiral column chromatography

column: CHIRALPAK IA(MB001) 20 mmID×250 mmL

solvent: CO₂/MeOH=600/400

backpressure: 100 bar

temperature: 35° C.

detection method: UV 220 nm

[α]_(D) ²⁵ −18.0 (c 0.2500, MeOH)

Example 8(1R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-methoxy-2-((6-oxo-1,6-dihydropyridin-3-yl)carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

N-(3-Fluoro-4-(trimethylsilyl)phenyl)-6-methoxy-2-((6-oxo-1,6-dihydropyridin-3-yl)carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(290 mg) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give the titlecompound (137.0 mg, >99% ee) as a white solid.

MS(API): Calculated 493.6. Found 492.2 (M−H).

purification condition by chiral column chromatography

column: CHIRALPAK ASH(LA005) 20 mmID×250 mmL

solvent: CO₂/MeOH/acetonitrile=600/200/200

backpressure: 100 bar

temperature: 35° C.

detection method: UV 220 nm

[α]_(D) ²⁵ −16.1 (c 0.2500, MeOH)

Example 9N-(4-tert-butyl-3-fluorophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

2-(tert-Butyl)aniline (10 g, 67.01 mmol) was slowly added dropwise tosulfuric acid (63.8 mL, 670.09 mmol) while the mixture was maintained at10° C. or below. Then, potassium nitrate (6.77 g, 67.01 mmol) was slowlyadded thereto while the mixture was maintained at 10° C. or below. Thereaction mixture was stirred at 5° C. for 30 min, and then at roomtemperature for 1 hr. The reaction mixture was poured into ice (about500 g), and the mixture was extracted with diethyl ether. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent; 20% ethylacetate/hexane), and crystallized from hexane to give2-(tert-butyl)-5-nitroaniline (12.26 g, 63.1 mmol, 94%) as a pale yellowsolid.

¹H NMR (300 MHz, CDCl₃): δ 1.44 (9H, s), 3.81-4.32 (2H, m), 7.34 (1H, d,J=8.7 Hz), 7.46 (1H, d, J=2.3 Hz), 7.49-7.59 (1H, m).

(Step 2)

A solution of 2-(tert-butyl)-5-nitroaniline (2054 mg, 10.58 mmol) andnitrosonium tetrafluoroborate (0.920 mL, 17.21 mmol) ino-dichlorobenzene (20 mL) was stirred at 0° C. for 1 hr. The reactionmixture was stirred at 110° C. for 1 hr, cooled, and poured into water.The mixture was extracted with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 0→10% ethylacetate/hexane) to give 1-(tert-butyl)-2-fluoro-4-nitrobenzene (1600 mg,8.11 mmol, 60.4%) as a brown oil.

¹H NMR (300 MHz, CDCl₃): δ 1.42 (9H, d, J=1.1 Hz), 7.48 (1H, t, J=8.3Hz), 7.87 (1H, dd, J=11.9, 2.5 Hz), 7.96 (1H, dd, J=8.7, 2.3 Hz).

(Step 3)

A solution of 1-(tert-butyl)-2-fluoro-4-nitrobenzene (1.6 g, 8.11 mmol)and 10% palladium-carbon (0.432 g, 0.20 mmol, 50% wet) in EtOH (20 mL)was stirred under hydrogen atmosphere (1 atm) at room temperature for 5hr. The catalyst was removed by filtration, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 0→20% ethylacetate/hexane) to give 4-(tert-butyl)-3-fluoroaniline (1.310 g, 7.83mmol, 97%) as a brown oil.

¹H NMR (300 MHz, CDCl₃): δ 1.32 (9H, d, J=1.1 Hz), 3.61 (2H, brs),6.26-6.46 (2H, m), 6.95-7.12 (1H, m).

(Step 4)

T3P (12.06 mL, 20.27 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (4.15 g, 13.51 mmol), 4-(tert-butyl)-3-fluoroaniline (2.26 g, 13.51mmol), DIEA (11.77 mL, 67.57 mmol) and DMAP (1.816 g, 14.87 mmol) inethyl acetate (95 mL), and the mixture was stirred at 70° C. for 15 hr.To the reaction mixture was added water, and the mixture was extractedthree times with ethyl acetate. The organic layer was washed with 10%aqueous citric acid solution, aqueous sodium hydrogen carbonate solutionand brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The precipitate was washed withIPE/hexane to give tert-butyl1-((4-(tert-butyl)-3-fluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(5.22 g, 11.43 mmol, 85%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 1.33 (9H, s), 1.52 (9H, s), 2.80-2.97 (2H,m), 3.52-3.77 (2H, m), 3.80 (3H, s), 5.61 (1H, brs), 6.72 (1H, d, J=2.3Hz), 6.81 (1H, dd, J=8.3, 2.6 Hz), 7.03 (1H, d, J=7.6 Hz), 7.14-7.22(2H, m), 7.39 (1H, dd, J=14.4, 2.3 Hz), 8.88 (1H, brs).

(Step 5)

TFA (3 mL) was added to tert-butyl1-((4-(tert-butyl)-3-fluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(214 mg, 0.47 mmol), and the mixture was stirred at room temperature for30 min. The reaction mixture was added to aqueous sodium hydrogencarbonate solution, and potassium carbonate was added thereto until thepH of the mixture became 8. Then, the mixture was extracted three timeswith a mixed solvent of ethyl acetate/THF. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure to giveN-(4-(tert-butyl)-3-fluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(155 mg, 0.435 mmol, 93%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.34 (9H, s), 2.20 (1H, brs), 2.69-2.80 (1H,m), 2.83-2.95 (1H, m), 3.14 (2H, t), 3.78 (3H, s), 4.62 (1H, s), 6.63(1H, d, J=2.6 Hz), 6.78 (1H, dd, J=8.7, 2.6 Hz), 7.10 (1H, dd), 7.18(1H, t), 7.44 (1H, dd, J=14.4, 2.3 Hz), 7.53 (1H, d, J=8.7 Hz), 9.35(1H, brs).

(Step 6)

HATU (195 mg, 0.51 mmol) was added to a solution ofN-(4-(tert-butyl)-3-fluorophenyl)-6-methoxy-,2,3,4-tetrahydroisoquinoline-1-carboxamide (152 mg, 0.43 mmol),3-hydroxy-1,2-oxazole-5-carboxylic acid (57.8 mg, 0.45 mmol) and DIEA(149 μL, 0.86 mmol) in DMF (2 mL) at room temperature, and the mixturewas stirred at room temperature for 15 hr. To the reaction mixture wasadded water, and the mixture was extracted three times with a mixedsolvent of ethyl acetate/THF. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 30→100% ethyl acetate/hexane), and theprecipitate was washed with diethyl ether to give the title compound(102.4 mg, 0.219 mmol, 51.4%) as white crystals.

MS(API): Calculated 467.5. Found 468.2 (M+H).

¹H NMR (300 MHz, CDCl₃): δ 1.33 (9H, s), 3.04-3.12 (2H, m), 3.82 (3H,s), 3.86-3.96 (1H, m), 4.08-4.19 (1H, m), 5.97 (1H, s), 6.55 (1H, s),6.77 (1H, d, J=2.3 Hz), 6.85 (1H, dd, J=8.5, 2.5 Hz), 7.09 (1H, dd),7.14-7.23 (2H, m), 7.40 (1H, dd, J=14.4, 1.9 Hz), 8.72 (1H, s), 10.24(1H, brs).

Example 10N-(4-tert-butyl-3-chlorophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

A solution of 2-(tert-butyl)-5-nitroaniline (4 g, 20.59 mmol), pentylnitrite (3.62 g, 30.89 mmol) and copper(I) chloride (2.039 g, 20.59mmol) in acetonitrile (100 mL) was stirred at 50° C. for 2 hr. To thereaction mixture was added 1N hydrochloric acid at room temperature, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 0→5% ethylacetate/hexane) to give 1-(tert-butyl)-2-chloro-4-nitrobenzene (1.760 g,8.24 mmol, 40.0%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.52 (9H, s), 7.60 (1H, d, J=9.1 Hz), 8.04(1H, dd, J=8.9, 2.5 Hz), 8.22 (1H, d, J=2.6 Hz).

(Step 2)

A solution of 1-(tert-butyl)-2-chloro-4-nitrobenzene (1.76 g, 8.24mmol), iron(II) chloride hexahydrate (0.045 g, 0.16 mmol) and activatedcarbon (300 mg) in a mixed solvent of THF (10 mL) and MeOH (10 mL) washeated under reflux for 15 min. Then, a solution of hydrazinemonohydrate (2.474 g, 49.42 mmol) in MeOH (5 mL) was added thereto, andthe mixture was heated under reflux for additional 40 min. The reactionmixture was cooled, and the insoluble substance was removed byfiltration. To the filtrate were added water and ethyl acetate, and theorganic layer was separated. The organic layer was washed with brine,and dried over sodium sulfate, and the solvent was evaporated underreduced pressure to give 4-(tert-butyl)-3-chloroaniline (1.420 g, 7.73mmol, 94%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.43 (9H, s), 3.58 (2H, brs), 6.51 (1H, dd,J=8.5, 2.5 Hz), 6.70 (1H, d, J=2.6 Hz), 7.18 (1H, d, J=8.3 Hz).

(Step 3)

T3P (0.729 mL, 1.22 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (251 mg, 0.82 mmol), 4-(tert-butyl)-3-chloroaniline (150 mg, 0.82mmol), DIEA (0.711 mL, 4.08 mmol) and DMAP (110 mg, 0.90 mmol) in ethylacetate (6 mL), and the mixture was stirred at 70° C. for 15 hr. To thereaction mixture was added water, and the mixture was extracted threetimes with ethyl acetate. The organic layer was washed with 10% aqueouscitric acid solution, aqueous sodium hydrogen carbonate solution andbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The precipitate was washed with IPE/hexane togive tert-butyl1-((4-(tert-butyl)-3-chlorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(331 mg, 0.700 mmol, 86%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 1.44 (9H, s), 1.52 (9H, s), 2.83-2.97 (2H,m), 3.55-3.76 (2H, m), 3.80 (3H, s), 5.59 (1H, brs), 6.72 (1H, d, J=2.3Hz), 6.81 (1H, dd, J=8.7, 2.6 Hz), 7.25-7.34 (3H, m), 7.60 (1H, brs),8.81 (1H, brs).

(Step 4)

TFA (4.5 mL) was added to tert-butyl1-((4-(tert-butyl)-3-chlorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(327 mg, 0.69 mmol), and the mixture was stirred at room temperature for30 min. The reaction mixture was added to ice and aqueous sodiumhydrogen carbonate solution, and 8N aqueous sodium hydroxide solutionand potassium carbonate were added thereto until the pH of the mixturebecame 8. Then, the mixture was extracted three times with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The precipitate was washed with IPE/hexane to giveN-(4-(tert-butyl)-3-chlorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(224 mg, 0.601 mmol, 87%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 1.44 (9H, s), 2.16 (1H, brs), 2.69-2.80 (1H,m), 2.83-2.94 (1H, m), 3.13 (2H, t, J=5.9 Hz), 3.78 (3H, s), 4.62 (1H,s), 6.63 (1H, d, J=2.6 Hz), 6.78 (1H, dd, J=8.3, 2.6 Hz), 7.32 (1H, d),7.40 (1H, dd), 7.53 (1H, d, J=8.7 Hz), 7.60 (1H, d, J=2.3 Hz), 9.34 (1H,s).

(Step 5)

HATU (270 mg, 0.71 mmol) was added to a mixture ofN-(4-(tert-butyl)-3-chlorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(221 mg, 0.59 mmol), 3-hydroxy-1,2-oxazole-5-carboxylic acid (80 mg,0.62 mmol) and DIEA (206 μL, 1.18 mmol) at room temperature, and themixture was stirred at room temperature for 15 hr. To the reactionmixture was added water, and the mixture was extracted three times withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 30→100% ethyl acetate/hexane), and theprecipitate was washed with IPE/hexane to give the title compound (198.3mg, 0.410 mmol, 69.1%) as white crystals.

MS(API): Calculated 483.9. Found 482.0 (M−H).

¹H NMR (300 MHz, CDCl₃): δ 1.43 (9H, s), 3.07 (2H, t, J=5.7 Hz), 3.82(3H, s), 3.92 (1H, dt, J=12.9, 6.2 Hz), 4.06-4.18 (1H, m), 5.96 (1H, s),6.55 (1H, s), 6.76 (1H, d, J=2.3 Hz), 6.85 (1H, dd, J=8.7, 2.3 Hz), 7.17(1H, d, J=8.7 Hz), 7.32 (2H, s), 7.60 (1H, s), 8.73 (1H, s), 10.44 (1H,brs).

Example 11N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

To a solution of 1-bromo-3-fluoro-5-methoxybenzene (15 g, 73.16 mmol),tris(2-methylphenyl)phosphane (1.781 g, 5.85 mmol) and ethyl acrylate(11.90 mL, 109.74 mmol) in TEA (135 mL) was added palladium(II) acetate(0.329 g, 1.46 mmol) under nitrogen gas atmosphere at room temperature,and the mixture was stirred at 90° C. for 2 days. The solvent wasevaporated under reduced pressure, the residue was diluted with water,and the mixture was extracted with ethyl acetate. The organic layer waswashed with water and brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography to give ethyl(E)-3-(3-fluoro-5-methoxyphenyl)acrylate (14.2 g, 63.3 mmol, 87%) as acolorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.34 (3H, t, J=7.2 Hz), 3.82 (3H, s), 4.27(2H, q, J=7.2 Hz), 6.40 (1H, d, J=16.2 Hz), 6.64 (1H, dt, J=10.2, 2.3Hz), 6.78-6.87 (2H, m), 7.58 (1H, d, J=16.2 Hz).

(Step 2)

A mixture of ethyl (E)-3-(3-fluoro-5-methoxyphenyl)acrylate (14.2 g,63.33 mmol) and 10% palladium-carbon (1.4 g, 0.66 mmol, 50% wet) in EtOH(300 mL) was stirred under hydrogen atmosphere (1 atm) at roomtemperature for 5 hr. The catalyst was removed by filtration throughCelite, and the filtrate was concentrated under reduced pressure to giveethyl 3-(3-fluoro-5-methoxyphenyl)propanoate (13.9 g, 61.4 mmol, 97%) asa colorless oil.

(Step 3)

To a solution of ethyl 3-(3-fluoro-5-methoxyphenyl)propanoate (13.9 g,61.44 mmol) in anhydrous THF (200 mL) was added dropwise 3Mmethylmagnesium bromide/diethyl ether solution (61.4 mL, 184.31 mmol) at0° C., and the mixture was stirred under nitrogen gas atmosphere at roomtemperature for 1 hr. To the reaction mixture were added water and ethylacetate, and the organic layer was separated. The organic layer wasdried over magnesium sulfate, and the solvent was evaporated underreduced pressure to give 4-(3-fluoro-5-methoxyphenyl)-2-methylbutan-2-ol(12.1 g, 57.01 mmol, 93%). This compound was used for the next stepwithout purification.

(Step 4)

A mixture of 4-(3-fluoro-5-methoxyphenyl)-2-methylbutan-2-ol (12.1 g,57.01 mmol) and PPA (100 g, 57.01 mmol) was stirred at 90° C. for 1 hr.The reaction mixture was added to ice-water, and the mixture wasextracted with ethyl acetate. The organic layer was dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent; ethyl acetate/hexane) to give7-fluoro-5-methoxy-1,1-dimethyl-2,3-dihydro-1H-indene (4.76 g, 24.51mmol, 43%) as a colorless oil.

(Step 5)

To a solution of 7-fluoro-5-methoxy-1,1-dimethyl-2,3-dihydro-1H-indene(4.76 g, 24.51 mmol) and 1-dodecanethiol (17.71 mL, 73.52 mmol) intoluene (50 mL) was added aluminium chloride (9.80 g, 73.52 mmol) at 0°C., and the mixture was stirred at room temperature for 2 hr. To thereaction mixture was added IN hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent; ethyl acetate/hexane) to give7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-ol (4.17 g, 23.14 mmol,94%) as a grayish white solid.

(Step 6)

To a solution of 7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-ol (4.17g, 23.14 mmol) in THF (80 mL) was added sodium hydride (60% oil, 1.111g, 27.77 mmol) at 0° C., and the mixture was stirred at room temperaturefor 15 min. Then,1,1,1-trifluoro-N-phenyl-N-(trifluoromethyl)sulfonylmethanesulfonamide(9.09 g, 25.45 mmol) was added thereto at 0° C., and the mixture wasstirred at room temperature for 2 hr. The reaction mixture was added toice-water, and the mixture was extracted with ethyl acetate. The organiclayer was dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent; ethyl acetate/hexane) to give7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yltrifluoromethanesulfonate (6.21 g, 19.89 mmol, 86%) as a colorless oil.

(Step 7)

A mixture of 7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yltrifluoromethanesulfonate (5.18 g, 16.59 mmol), diphenylmethanimine(3.61 g, 19.91 mmol), Pd₂(dba)₃ (0.759 g, 0.83 mmol), BINAP (1.033 g,1.66 mmol), sodium t-butoxide (2.391 g, 24.88 mmol) and toluene (75 mL)was stirred at 80° C. for 2 hr. The reaction mixture was added to water,and the mixture was extracted with ethyl acetate. The organic layer wasdried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was dissolved in THF (200 mL),and 1N hydrochloric acid (83 mL, 82.94 mmol) was added thereto. Themixture was stirred at room temperature for 30 min, and 1N aqueoussodium hydroxide solution was added thereto until the mixture becamebasic. The mixture was extracted with ethyl acetate. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 0→10% ethylacetate/hexane) to give7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine (1.92 g, 10.71 mmol,65%) as an orange oil.

¹H NMR (300 MHz, CDCl₃): δ 1.34 (6H, s), 1.89 (2H, t, J=7.4 Hz), 2.82(2H, t, J=7.2 Hz), 3.61 (2H, brs), 6.13-6.21 (1H, m), 6.28-6.33 (1H, m).

(Step 8)

To a solution of 7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine (100mg, 0.56 mmol),2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (206 mg, 0.67 mmol), DMAP (75.0 mg, 0.61 mmol) and DIEA (0.487 mL,2.79 mmol) in ethyl acetate (3.0 mL) was added T3P (0.656 mL, 1.12mmol), and the mixture was stirred at 80° C. for 2 hr. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→20% ethyl acetate/hexane) to givetert-butyl1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(139.7 mg, 0.298 mmol, 53.4%) as a white solid.

MS(API): Calculated 468.56. Found 467.3 (M−H).

(Step 9)

To a solution of tert-butyl1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(139 mg, 0.30 mmol) in ethyl acetate (2.0 mL) was added 4N hydrogenchloride/ethyl acetate (2.0 mL, 8.00 mmol), and the mixture was stirredovernight at room temperature. The precipitate was collected byfiltration with ethyl acetate to giveN-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (102.2 mg, 0.252 mmol, 85%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 1.32 (6H, s), 1.90 (2H, t, J=7.2 Hz), 2.91(2H, t, J=7.2 Hz), 2.95-3.03 (1H, m), 3.04-3.19 (1H, m), 3.36-3.46 (1H,m), 3.64-3.73 (1H, m), 3.74 (3H, s), 5.23 (1H, s), 6.75-6.95 (2H, m),7.20-7.45 (3H, m), 9.36 (1H, brs), 10.10 (1H, brs), 11.37 (1H, s).

(Step 10)

To a solution ofN-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (100 mg, 0.25 mmol), DIEA (0.127 mL, 0.74 mmol),3-hydroxy-1,2-oxazole-5-carboxylic acid (35.1 mg, 0.27 mmol) and DIEA(0.127 mL, 0.74 mmol) in DMF (2.0 mL) was added HATU (113 mg, 0.30 mmol)at 0° C., and the mixture was stirred at room temperature for 2 hr. Tothe reaction mixture were added water and ethyl acetate, and the organiclayer was separated. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→50% ethyl acetate/hexane) to givethe title compound (78.2 mg, 0.163 mmol, 66.0%) as white crystals.

MS(API): Calculated 479.5. Found 480.1 (M+H).

¹H NMR (300 MHz, DMSO-d): δ 1.28 (6H, d, J=1.5 Hz), 1.87 (2H, t, J=7.4Hz), 2.71-2.95 (3H, m), 3.01-3.24 (1H, m), 3.61-3.87 (4H, m), 4.03-4.24(1H, m), 5.50-5.75 (1H, m), 6.32-6.64 (1H, m), 6.75-6.92 (2H, m),7.05-7.30 (2H, m), 7.46-7.58 (1H, m), 10.22-10.66 (1H, m), 11.78 (1H,brs).

Example 12 N-(4-tert-butyl-3,5-difluorophenyl)-2-((3-hydroxy-,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

To a solution of 3,5-difluorophenol (17.0 g, 130.68 mmol) in2-methoxy-2-methylpropane (34 mL, 285.43 mmol) was slowly addedzirconium(IV) chloride (15.23 g, 65.34 mmol) so that the mixture wasmaintained at 30 to 40° C. The mixture was stirred at room temperaturefor 2 hr, and zirconium(IV) chloride (15.23 g, 65.34 mmol) was slowlyadded thereto. The mixture was stirred at room temperature for 2 hr, andthe reaction mixture was poured into ice and 8N aqueous sodium hydroxidesolution (90 mL). Diethyl ether (about 400 mL) was added thereto, andthe insoluble substance was removed by filtration. The filtrate waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 0→10% ethylacetate/hexane) to give 4-(tert-butyl)-3,5-difluorophenol (16.80 g, 90mmol, 69.0%) as a brown oil.

¹H NMR (300 MHz, CDCl₃): δ 1.42 (9H, t, J=2.3 Hz), 5.07-5.26 (1H, m),6.24-6.42 (2H, m).

(Step 2)

To a solution of 4-(tert-butyl)-3,5-difluorophenol (16.8 g, 90.23 mmol)in THF (168 mL) was added sodium hydride (60% oil, 4.33 g, 108.27 mmol)at 0° C., and1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(35.5 g, 99.25 mmol) was added thereto. The reaction mixture was stirredat room temperature for 2 hr, and poured into aqueous ammonium chloridesolution. The mixture was extracted with ethyl acetate, the organiclayer was washed with aqueous sodium hydrogen carbonate solution, anddried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent; hexane) to give4-(tert-butyl)-3,5-difluorophenyl trifluoromethanesulfonate (8.14 g,25.6 mmol, 28.3%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 1.46 (9H, t, J=2.3 Hz), 6.80 (2H, d, J=10.2Hz).

(Step 3)

A solution of XANTPHOS (1.407 g, 2.43 mmol), diphenylmethanimine (4.06mL, 24.32 mmol), cesium carbonate (15.85 g, 48.64 mmol),4-(tert-butyl)-3,5-difluorophenyl trifluoromethanesulfonate (5.16 g,16.21 mmol) and Pd₂(dba)₃ (0.742 g, 0.81 mmol) in THF (50 mL) was heatedunder reflux overnight. The reaction mixture was neutralized withaqueous sodium hydrogen carbonate solution. To the reaction mixture wasadded ethyl acetate, and the organic layer was separated. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue wereadded THF (50.00 mL) and 6N hydrochloric acid (5 mL, 30 mmol), and themixture was stirred at room temperature for 2 hr. The reaction mixturewas neutralized with aqueous sodium hydrogen carbonate solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 5→15% ethylacetate/hexane) to give 4-(tert-butyl)-3,5-difluoroaniline (2.100 g,11.34 mmol, 69.9%) as a pale yellow oil.

¹H NMR (300 MHz, DMSO-d₆): δ 1.33 (9H, t, J=2.1 Hz), 5.46 (2H, s),6.02-6.18 (2H, m).

(Step 4)

To a solution of 4-(tert-butyl)-3,5-difluoroaniline (150 mg, 0.81 mmol),2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (299 mg, 0.97 mmol), DMAP (109 mg, 0.89 mmol) and DIEA (0.707 mL,4.05 mmol) in ethyl acetate (3.0 mL) was added T3P (0.953 mL, 1.62mmol), and the mixture was stirred at 80° C. for 2 hr. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→20% ethyl acetate/hexane) to givetert-butyl1-((4-(tert-butyl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(253.6 mg, 0.534 mmol, 66.0%) as white crystals.

MS(API): Calculated 474.54. Found 473.3 (M−H).

(Step 5)

To a solution of tert-butyl1-((4-(tert-butyl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(250 mg, 0.53 mmol) in ethyl acetate (5.0 mL) was added 4N hydrogenchloride/ethyl acetate (5.0 mL, 20.00 mmol), and the mixture was stirredat room temperature for 5 hr. The precipitate was collected byfiltration with ethyl acetate to giveN-(4-(tert-butyl)-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (135.2 mg, 0.329 mmol, 62.5%) as white crystals.

¹H NMR (300 MHz, DMSO-d): δ 1.41 (9H, t, J=1.9 Hz), 2.89-3.19 (2H, m),3.38-3.51 (1H, m), 3.63-3.81 (4H, m), 5.24 (1H, s), 6.80-6.93 (2H, m),7.22-7.42 (3H, m), 9.44 (1H, brs), 10.03 (1H, brs), 11.72 (1H, s).

(Step 6)

To a solution ofN-(4-(tert-butyl)-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (130 mg, 0.32 mmol), DIEA (0.162 mL, 0.95 mmol) and3-hydroxy-1,2-oxazole-5-carboxylic acid (53.1 mg, 0.41 mmol) in DMF (2.0mL) was added HATU (144 mg, 0.38 mmol), and the mixture was stirred atroom temperature for 2 hr. To the reaction mixture were added water andethyl acetate, and the organic layer was separated. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 0→50% ethylacetate/hexane) to give the title compound (70.2 mg, 0.145 mmol, 45.7%)as white crystals.

MS(API): Calculated 485.5. Found 486.1 (M+H).

¹H NMR (300 MHz, DMSO-d): δ 1.38 (9H, t, J=1.9 Hz), 3.02-3.23 (1H, m),3.64-3.83 (4H, m), 4.09-4.23 (1H, m), 5.52-5.69 (1H, m), 6.38-6.62 (1H,m), 6.79-6.92 (2H, m), 7.12-7.27 (2H, m), 7.46-7.56 (1H, m), 7.95 (1H,s), 10.44-10.87 (1H, m), 11.81 (1H, brs).

Example 13(1R)—N-(4-tert-butyl-3-fluorophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

HATU (230 mg, 0.61 mmol) was added to a solution of(R)—N-(4-(tert-butyl)-3-fluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(180 mg, 0.51 mmol), 3-hydroxy-1,2-oxazole-5-carboxylic acid (68.4 mg,0.53 mmol) and DIEA (176 μL, 1.01 mmol) in DMF (2.5 mL) at roomtemperature, and the mixture was stirred at room temperature for 15 hr.To the reaction mixture was added water, and the mixture was extractedthree times with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 30→100% ethyl acetate/hexane) to givethe title compound (99.1 mg, 0.212 mmol, 42.0%) as a white solid.

MS(API): Calculated 467.5. Found 468.2 (M+H).

¹H NMR (300 MHz, CDCl₃): δ 1.32 (9H, s), 3.09 (2H, brs), 3.81 (3H, s),3.92-4.03 (1H, m), 4.07-4.17 (1H, m), 5.98 (1H, s), 6.56 (1H, s), 6.77(1H, s), 6.84 (1H, dd, J=8.7, 2.3 Hz), 7.07 (1H, dd), 7.13-7.22 (2H, m),7.38 (1H, dd, J=14.4, 1.9 Hz), 8.84 (1H, s), 10.52 (1H, brs).

[α]_(D) ²⁵ −13.4 (c 0.2500, MeOH)

Example 14(1S)—N-(4-tert-butyl-3-fluorophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

The title compound was synthesized using(S)—N-(4-(tert-butyl)-3-fluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide,by the reaction and purification in the same manner as in Examples 1 and25.

MS(API): Calculated 467.5. Found 468.1 (M+H).

The compounds described in Examples 15 to 24 were synthesized by thereaction and purification in the same manner as in Examples 1 and 25.

Example 15(1R)—N-(4-tert-butyl-3-fluorophenyl)-2-((2,4-dioxo-1,3-thiazolidin-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(a mixture of two diastereomers) Example 16(1R)—N-(4-tert-butyl-3-fluorophenyl)-2-((2,6-dioxopiperidin-4-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamideExample 17(1R)—N¹-(4-tert-butyl-3-fluorophenyl)-6-methoxy-N²-(pyridazin-3-yl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxamideExample 18(1R)—N-(4-tert-butyl-3-fluorophenyl)-2-((2,5-dioxoimidazolidin-4-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(a mixture of two diastereomers) Example 19(1R)—N-(4-tert-butyl-3-fluorophenyl)-2-((2,4-dioxoimidazolidin-1-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamideExample 20(1R)—N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-((5-oxopyrrolidin-3-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(a mixture of two diastereomers) Example 21(1R)—N¹-(4-tert-butyl-3-fluorophenyl)-6-methoxy-N²-(1-methyl-1H-pyrazol-3-yl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxamideExample 22(1R)—N-(4-tert-butyl-3-fluorophenyl)-2-((5,5-dimethyl-2,4-dioxo-1,3-oxazolidin-3-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamideExample 23(1R)—N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-((2-oxoimidazolidin-1-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamideExample 24(1R)—N-(4-tert-butyl-3-fluorophenyl)-2-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamideExample 25(1R)—N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-(((3S)-5-oxopyrrolidin-3-yl)carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

tert-Butyl1-((4-(tert-butyl)-3-fluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(5.00 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((4-(tert-butyl)-3-fluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(2.38 g, >99.9% ee) as a white solid.

purification condition by chiral column chromatography

column: CHIRALCEL OD (NL001) 50 mmID×500 mmL

solvent: hexane/EtOH=600/400

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 2)

TFA (28 mL) was added to tert-butyl(R)-1-((4-(tert-butyl)-3-fluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(2.33 g, 5.10 mmol), and the mixture was stirred at room temperature for30 min. The reaction mixture was added to ice and aqueous sodiumhydrogen carbonate solution, and 8N aqueous sodium hydroxide solutionand potassium carbonate were added thereto until the pH of the mixturebecame 8. Then, the mixture was extracted three times with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reduced pressureto give(R)—N-(4-(tert-butyl)-3-fluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(1.69 g, 4.74 mmol, 93%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.34 (9H, s), 2.05 (1H, brs), 2.69-2.80 (1H,m), 2.84-2.95 (1H, m), 3.14 (2H, t), 3.78 (3H, s), 4.64 (1H, s), 6.64(1H, d, J=2.6 Hz), 6.78 (1H, dd, J=8.7, 2.6 Hz), 7.11 (1H, dd), 7.18(1H, t), 7.44 (1H, dd, J=14.4, 2.3 Hz), 7.53 (1H, d, J=8.7 Hz), 9.36(1H, s).

(Step 3)

HATU (77 mg, 0.20 mmol) was added to a solution of(R)—N-(4-(tert-butyl)-3-fluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(60 mg, 0.17 mmol), (S)-5-oxopyrrolidine-3-carboxylic acid (22.82 mg,0.18 mmol) and DIEA (59 μL, 0.34 mmol) in DMF (0.9 mL) at roomtemperature, and the mixture was stirred at room temperature for 15 hr.To the reaction mixture was added water, and the mixture was extractedthree times with a mixed solvent of ethyl acetate/THF. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 0→30% ethylacetate/hexane), and the precipitate was washed with diethyl ether/IPEto give the title compound (65.9 mg, 0.141 mmol, 84%) as white crystals.

MS(API): Calculated 467.5. Found 466.0 (M−H).

¹H NMR (300 MHz, CDCl₃): δ 1.30 (9H, s), 2.61 (1H, dd, J=17.0, 9.1 Hz),2.78-2.92 (2H, m), 3.14-3.25 (1H, m), 3.59-3.76 (4H, m), 3.79 (3H, s),3.96 (1H, ddd, J=12.1, 7.6, 4.5 Hz), 5.98 (1H, s), 6.00 (1H, s), 6.74(1H, d, J=2.6 Hz), 6.83 (1H, dd, J=8.5, 2.5 Hz), 6.96 (1H, dd, J=8.5,2.1 Hz), 7.11 (1H, t), 7.24-7.28 (1H, m), 7.32 (1H, dd, J=14.4, 2.3 Hz),9.06 (1H, s).

Example 26(1R)—N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-(((3R)-5-oxopyrrolidin-3-yl)carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

HATU (77 mg, 0.20 mmol) was added to a solution of(R)—N-(4-(tert-butyl)-3-fluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(60 mg, 0.17 mmol), (R)-5-oxopyrrolidine-3-carboxylic acid (22.82 mg,0.18 mmol) and DIEA (59 μL, 0.34 mmol) in DMF (0.9 mL) at roomtemperature, and the mixture was stirred for 15 hr. To the reactionmixture was added water, and the mixture was extracted three times witha mixed solvent of ethyl acetate/THF. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 0→10% MeOH/ethyl acetate), andthe precipitate was washed with diethyl ether/IPE to give the titlecompound (64.0 mg, 0.137 mmol, 81%) as white crystals.

MS(API): Calculated 467.5. Found 466.0 (M−H).

¹H NMR (300 MHz, CDCl₃): δ 1.30 (9H, s), 2.55-2.65 (1H, m), 2.70-2.80(1H, m), 2.89 (1H, ddd, J=15.8, 7.1, 4.7 Hz), 3.15-3.26 (1H, m),3.64-3.77 (4H, m), 3.80 (3H, s), 3.96 (1H, ddd, J=12.1, 7.4, 4.7 Hz),5.82 (1H, s), 5.97 (1H, s), 6.74 (1H, d, J=2.3 Hz), 6.83 (1H, dd, J=8.5,2.5 Hz), 6.97 (1H, dd, J=8.5, 2.1 Hz), 7.09 (1H, t), 7.23-7.31 (2H, m),9.12 (1H, s).

Example 27(1R)—N-(4-tert-butyl-3-fluorophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

n-BuLi (5.27 mL, 8.43 mmol) was added to a solution of diisopropylamine(1.301 mL, 9.20 mmol) in THF (40 mL) at −78° C. under argon gasatmosphere, and the mixture was stirred for 20 min. Then, a solution of3-(benzyloxy)-5-methyl-1,2-oxazole (1450 mg, 7.66 mmol) in THF (10.0 mL)was added thereto at −78° C., and the mixture was stirred for 50 min.Then, a solution of ethyl chloroformate (0.875 mL, 9.20 mmol) in THF(5.0 mL) was added thereto at −78° C., and the mixture was stirred for 2hr. To the reaction mixture was added aqueous ammonium chloridesolution, and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 5→20%ethyl acetate/hexane) to give diethyl2-(3-(benzyloxy)-1,2-oxazol-5-yl)malonate (391 mg, 1.173 mmol, 15.31%)as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.23-1.37 (6H, m), 4.19-4.33 (4H, m), 4.77(1H, s), 5.27 (2H, s), 6.14 (1H, s), 7.29-7.50 (5H, m).

(Step 2)

2N Aqueous sodium hydroxide solution (3.52 mL, 7.04 mmol) was added to asolution of diethyl 2-(3-(benzyloxy)-1,2-oxazol-5-yl)malonate (391 mg,1.17 mmol) in EtOH (3.5 mL), and the mixture was stirred at roomtemperature for 3 hr. THF (1.50 mL) was added thereto, and the mixturewas stirred at room temperature for 1 hr, and then overnight at 50° C.The reaction mixture was neutralized with 1N hydrochloric acid, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was crystallized fromhexane/IPE to give 2-(3-(benzyloxy)-1,2-oxazol-5-yl)acetic acid (154 mg,0.660 mmol, 56.3%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 3.79 (2H, s), 5.26 (2H, s), 5.97 (1H, s),7.30-7.50 (5H, m) (The peak derived from COOH was not observed).

(Step 3)

HATU (154 mg, 0.40 mmol) was added to a solution of(R)—N-(4-(tert-butyl)-3-fluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(120 mg, 0.34 mmol), 2-(3-(benzyloxy)-1,2-oxazol-5-yl)acetic acid (82mg, 0.35 mmol) and DIEA (117 μL, 0.67 mmol) in DMF (1.7 mL) at roomtemperature, and the mixture was stirred at room temperature for 15 hr.To the reaction mixture was added water, and the mixture was extractedthree times with a mixed solvent of ethyl acetate/THF. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 8→50% ethylacetate/hexane), and the precipitate was washed with diethyl ether/IPEto give(R)-2-(2-(3-(benzyloxy)-1,2-oxazol-5-yl)acetyl)-N-(4-(tert-butyl)-3-fluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(160 mg, 0.280 mmol, 83%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 1.30 (9H, s), 2.81-2.91 (1H, m), 3.19 (1H,ddd, J=15.5, 7.7, 4.7 Hz), 3.67-3.75 (1H, m), 3.77 (3H, s), 3.89-4.03(3H, m), 5.25 (2H, s), 5.99 (2H, d, J=5.7 Hz), 6.73 (1H, d, J=2.3 Hz),6.83 (1H, dd, J=8.3, 2.6 Hz), 6.95 (1H, dd, J=8.5, 2.1 Hz), 7.09 (1H,t), 7.21-7.30 (2H, m), 7.33-7.45 (5H, m), 8.96 (1H, s).

(Step 4)

To a solution of(R)-2-(2-(3-(benzyloxy)-1,2-oxazol-5-yl)acetyl)-N-(4-(tert-butyl)-3-fluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(157 mg, 0.27 mmol) in a mixed solvent of MeOH (2.8 mL) and THF (2.8 mL)was added 5% palladium-barium sulfate (200 mg, 0.094 mmol), and themixture was stirred under hydrogen atmosphere (1 atm) at roomtemperature for 3 hr. The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (solvent gradient;30→100% ethyl acetate/hexane), and the precipitate was washed withIPE/hexane to give the title compound (103.1 mg, 0.214 mmol, 78%) aswhite crystals.

MS(API): Calculated 481.5. Found 480.0 (M−H).

¹H NMR (300 MHz, DMSO-dr): δ 1.29 (9H, s), 2.77-2.89 (1H, m), 3.08-3.20(1H, m), 3.55-3.67 (1H, m), 3.73 (3H, s), 3.91-4.14 (3H, m), 5.67 (1H,s), 5.91 (1H, s), 6.80-6.86 (2H, m), 7.18-7.29 (2H, m), 7.41-7.52 (2H,m), 10.54 (1H, s), 11.14 (1H, brs).

[α]_(D) ²⁵ +8.8 (c 0.2500, MeOH)

Example 28(1R)—N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-((5-methyl-1,3,4-oxadiazol-2-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

To a solution of ethyl 2-(5-methyl-1,3,4-oxadiazol-2-yl)acetate (279 mg,1.64 mmol) in a mixed solvent of water (2 mL) and THF (1 mL) was addedlithium hydroxide monohydrate (68.9 mg, 1.64 mmol), and the mixture wasstirred at room temperature for 1 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was subjected toazeotropy with toluene to give lithium2-(5-methyl-1,3,4-oxadiazol-2-yl)acetate (250 mg, 1.689 mmol, 103%) as awhite solid.

¹H NMR (300 MHz, DMSO-d): δ 2.41 (3H, s), 3.35 (2H, s).

(Step 2)

HATU (77 mg, 0.20 mmol) was added to a solution of(R)—N-(4-(tert-butyl)-3-fluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(60 mg, 0.17 mmol), lithium 2-(5-methyl-1,3,4-oxadiazol-2-yl)acetate(26.2 mg, 0.18 mmol) and DIEA (59 μL, 0.34 mmol) in DMF (0.9 mL) at roomtemperature, and the mixture was stirred at room temperature for 15 hr.To the reaction mixture was added water, and the mixture was extractedthree times with a mixed solvent of ethyl acetate/THF. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 30→100% ethylacetate/hexane), and the precipitate was washed with diethylether/hexane to give the title compound (61.9 mg, 0.129 mmol, 77%) aswhite crystals.

MS(API): Calculated 480.5. Found 481.1 (M+H).

¹H NMR (300 MHz, CDCl₃): δ 1.31 (9H, s), 2.51 (3H, s), 2.83-2.93 (1H,m), 3.17 (1H, ddd, J=15.6, 7.8, 4.9 Hz), 3.71 (1H, ddd, J=12.1, 7.7, 4.7Hz), 3.80 (3H, s), 3.96 (1H, ddd, J=12.0, 6.9, 4.9 Hz), 4.04-4.21 (2H,m), 6.00 (1H, s), 6.71 (1H, d, J=2.6 Hz), 6.84 (1H, dd, J=8.7, 2.6 Hz),7.08-7.14 (2H, m), 7.23-7.3-7.28 (1H, m), 7.35-7.42 (1H, m), 9.21 (1H,s).

Example 29(1R)—N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-((6-oxopyrimidin-1(6H)-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

HATU (77 mg, 0.20 mmol) was added to a solution of(R)—N-(4-(tert-butyl)-3-fluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(60 mg, 0.17 mmol), 2-(6-oxopyrimidin-1(6H)-yl)acetic acid (27.2 mg,0.18 mmol) and DIEA (59 μL, 0.34 mmol) in DMF (0.9 mL) at roomtemperature, and the mixture was stirred at room temperature for 15 hr.To the reaction mixture was added water, and the mixture was extractedthree times with a mixed solvent of ethyl acetate/THF. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 0→5% MeOH/ethylacetate), and the precipitate was washed with diethyl ether/hexane togive the title compound (62.3 mg, 0.126 mmol, 75%) as white crystals.

MS(API): Calculated 492.5. Found 491.1 (M−H).

¹H NMR (300 MHz, CDCl₃): δ 1.31 (9H, s), 2.87-3.00 (1H, m), 3.16-3.28(1H, m), 3.72-3.80 (1H, m), 3.81 (3H, s), 4.12 (1H, dt, J=11.5, 5.6 Hz),4.71-4.90 (2H, m), 5.93 (1H, s), 6.51-6.56 (1H, m), 6.75 (1H, d, J=2.6Hz), 6.82 (1H, dd, J=8.5, 2.5 Hz), 7.04 (1H, dd), 7.13 (1H, t), 7.22(1H, d, J=8.3 Hz), 7.33 (1H, dd, J=14.5, 2.1 Hz), 7.98 (1H, d, J=6.8Hz), 8.16 (1H, s), 8.65 (1H, s).

Example 30(1R)—N-(4-tert-butyl-3-fluorophenyl)-2-(3-hydroxypropanoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

HATU (77 mg, 0.20 mmol) was added to a solution of(R)—N-(4-(tert-butyl)-3-fluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(60 mg, 0.17 mmol), 3.6M aqueous 3-hydroxypropanoic acid solution (51.4μL, 0.19 mmol) and DIEA (59 μL, 0.34 mmol) in DMF (0.9 mL) at roomtemperature, and the mixture was stirred at room temperature for 15 hr.To the reaction mixture was added water, and the mixture was extractedthree times with a mixed solvent of ethyl acetate/THF. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 30→100% ethylacetate/hexane) to give the title compound (53.6 mg, 0.125 mmol, 74.3%)as a white solid.

MS(API): Calculated 428.5. Found 427.1 (M−H).

¹H NMR (300 MHz, CDCl₃): δ 1.32 (9H, s), 2.59-2.79 (2H, m), 2.80 (1H,s), 2.83-2.93 (1H, m), 3.04-3.15 (2H, m), 3.66 (1H, ddd, J=12.2, 7.5,4.9 Hz), 3.76-3.86 (4H, m), 3.92-4.02 (1H, m), 6.00 (1H, s), 6.75 (1H,d, J=2.6 Hz), 6.83 (1H, dd, J=8.5, 2.5 Hz), 7.02 (1H, dd), 7.11-7.22(2H, m), 7.36 (1H, dd, J=14.4, 2.3 Hz), 8.80 (1H, s).

Example 31(1R)—N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-(3-(methylsulfonyl)propanoyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

The title compound was synthesized by the reaction and purification inthe same manner as in Examples 1 and 25.

Example 32(1R)—N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-((6-methoxypyridin-3-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

HATU (154 mg, 0.40 mmol) was added to a solution of(R)—N-(4-(tert-butyl)-3-fluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(120 mg, 0.34 mmol), 2-(6-methoxypyridin-3-yl)acetic acid (59.1 mg, 0.35mmol) and DIEA (117 μL, 0.67 mmol) in DMF (1.7 mL) at room temperature,and the mixture was stirred at room temperature for 15 hr. To thereaction mixture was added water, and the mixture was extracted threetimes with a mixed solvent of ethyl acetate/THF. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 20→80% ethylacetate/hexane), and the precipitate was washed with diethylether/hexane to give the title compound (139.4 mg, 0.276 mmol, 82%) aswhite crystals.

MS(API): Calculated 505.6. Found 506.2 (M+H).

¹H NMR (300 MHz, CDCl₃): δ 1.30 (9H, s), 2.73-2.84 (1H, m), 3.11-3.23(1H, m), 3.68-3.82 (6H, m), 3.91-4.01 (4H, m), 5.97 (1H, s), 6.70-6.76(3H, m), 6.89 (1H, dd, J=8.7, 2.3 Hz), 7.04-7.12 (2H, m), 7.23 (1H, dd),7.54 (1H, dd, J=8.5, 2.5 Hz), 8.05 (1H, d, J=2.3 Hz), 9.21 (1H, s).

Example 33(1R)—N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-((6-oxo-1,6-dihydropyridin-3-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

Chlorotrimethylsilane (75 μL, 0.59 mmol) was added to a solution of(1R)—N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-((6-methoxypyridin-3-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(100 mg, 0.20 mmol) and sodium iodide (89 mg, 0.59 mmol) in acetonitrile(2.5 mL), and the mixture was stirred at 70° C. for 4 hr. To thereaction mixture was added 2% aqueous Na₂SO₃ solution, and the mixturewas extracted three times with a mixed solvent of ethyl acetate/THF. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The precipitatewas washed with diethyl ether/hexane to give the title compound (47.8mg, 0.097 mmol, 49.2%) as white crystals.

MS(API): Calculated 491.6. Found 492.2 (M+H).

¹H NMR (300 MHz, CDCl₃): δ 1.29 (9H, s), 2.82 (1H, dt, J=15.3, 5.0 Hz),3.30-3.42 (1H, m), 3.55-3.66 (3H, m), 3.77 (3H, s), 4.05-4.15 (1H, m),5.84 (1H, s), 6.61 (1H, d, J=9.4 Hz), 6.71 (1H, d, J=2.3 Hz), 6.76 (1H,dd, J=8.3, 2.6 Hz), 7.07-7.17 (2H, m), 7.29-7.44 (4H, m), 10.07 (1H, s),12.00 (1H, brs).

Example 344-((1R)-1-((4-tert-butyl-3-fluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutanoicacid

Succinic anhydride (17.69 mg, 0.18 mmol) was added to a solution of(R)—N-(4-(tert-butyl)-3-fluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(60 mg, 0.17 mmol) and TEA (26 μL, 0.19 mmol) in THF (1.5 mL), and themixture was stirred at room temperature for 4 hr. To the reactionmixture was added 0.1N hydrochloric acid, and the mixture was extractedthree times with a mixed solvent of ethyl acetate/THF. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (Diol, solvent gradient; 0→10%MeOH/ethyl acetate), and the precipitate was washed with diethylether/hexane to give the title compound (63.1 mg, 0.138 mmol, 82%) aswhite crystals.

MS(API): Calculated 456.5. Found 455.1 (M−H).

¹H NMR (300 MHz, CDCl₃): δ 1.30 (9H, s), 2.64-2.74 (1H, m), 2.76-2.93(4H, m), 3.06-3.18 (1H, m), 3.68 (1H, ddd, J=12.2, 7.6, 5.1 Hz), 3.80(3H, s), 3.81-3.92 (1H, m), 5.99 (1H, s), 6.74 (1H, d, J=2.6 Hz), 6.81(1H, dd, J=8.5, 2.5 Hz), 7.03 (1H, dd), 7.12 (1H, t), 7.22 (1H, d, J=8.3Hz), 7.31 (1H, dd, J=14.4, 2.3 Hz), 8.89 (1H, s) (The exchangeable 1Hwas not observed).

Example 35N-(4-tert-butyl-3-fluorophenyl)-4-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-carboxamide(Step 1)

Boc₂O (2.415 g, 11.06 mmol) was added to a solution of methyl8-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylate (2.50g, 10.54 mmol) in THF (30 mL), and the mixture was stirred at roomtemperature for 3 hr. The reaction mixture was concentrated underreduced pressure, and the precipitate was crystallized from IPE/hexaneto give 5-methyl 4-tert-butyl8-methoxy-2,3-dihydrobenzo[f][1,4]oxazepine-4,5(5H)-dicarboxylate (2.97g, 8.80 mmol, 84%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 1.44-1.49 (9H, m), 3.69-3.73 (3H, m),3.74-4.00 (6H, m), 4.23-4.38 (1H, m), 5.54-5.97 (1H, m), 6.53-6.59 (1H,m), 6.59-6.66 (1H, m), 7.09-7.24 (1H, m).

(Step 2)

2N Aqueous lithium hydroxide solution (26.3 mL, 52.64 mmol) was added toa solution of 5-methyl 4-tert-butyl8-methoxy-2,3-dihydrobenzo[f][1,4]oxazepine-4,5(5H)-dicarboxylate (2.96g, 8.77 mmol) in a mixed solvent of EtOH (14 mL) and THF (14 mL), andthe mixture was stirred at room temperature for 1.5 hr. To the reactionmixture was added ice, and 2N hydrochloric acid was added thereto untilthe pH of the mixture became 3. Then, the mixture was extracted threetimes with a mixed solvent of ethyl acetate/THF. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was crystallized fromIPE/hexane to give4-(tert-butoxycarbonyl)-8-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylicacid (2.77 g, 8.57 mmol, 98%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 1.46 (9H, s), 3.71-3.81 (4H, m), 3.86-3.97(2H, m), 4.23-4.39 (1H, m), 5.54-6.00 (1H, m), 6.54-6.67 (2H, m),7.14-7.24 (1H, m) (The exchangeable 1H was not observed).

(Step 3)

T3P (1.909 mL, 3.21 mmol) was added to a solution of4-(tert-butoxycarbonyl)-8-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylicacid (692 mg, 2.14 mmol), 4-(tert-butyl)-3-fluoroaniline (358 mg, 2.14mmol), DIEA (1.864 mL, 10.70 mmol) and DMAP (288 mg, 2.35 mmol) in ethylacetate (17 mL), and the mixture was stirred at 65° C. for 15 hr. To thereaction mixture was added water, and the mixture was extracted threetimes with ethyl acetate. The organic layer was washed with brine, anddried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 30→50% ethyl acetate/hexane) to givetert-butyl5-((4-(tert-butyl)-3-fluorophenyl)carbamoyl)-8-methoxy-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(887 mg, 1.877 mmol, 88%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.33 (9H, s), 1.47 (9H, s), 3.56-3.78 (1H,m), 3.81 (3H, s), 3.83-3.95 (2H, m), 4.31 (1H, brs), 5.46-6.00 (1H, m),6.64 (1H, d, J=2.3 Hz), 6.69 (1H, dd, J=8.3, 2.3 Hz), 6.96 (1H, d, J=7.9Hz), 7.13-7.24 (2H, m), 7.31 (1H, dd, J=14.4, 2.3 Hz), 7.71 (1H, brs).

(Step 4)

TFA (10 mL, 134.6 mmol) was added to tert-butyl5-((4-(tert-butyl)-3-fluorophenyl)carbamoyl)-8-methoxy-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(882 mg, 1.87 mmol), and the mixture was stirred at room temperature for20 min. The reaction mixture was added to ice and aqueous sodiumhydrogen carbonate solution, and potassium carbonate was added theretountil the pH of the mixture became 8. Then, the mixture was extractedthree times with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was crystallized from IPE/hexane to giveN-(4-(tert-butyl)-3-fluorophenyl)-8-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxamide(636 mg, 1.708 mmol, 91%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 1.35 (9H, s), 1.81 (1H, brs), 3.13-3.31 (2H,m), 3.80 (3H, s), 3.96-4.14 (2H, m), 4.69 (1H, s), 6.61-6.66 (2H, m),7.12 (1H, dd), 7.18-7.25 (2H, m), 7.46 (1H, dd, J=14.4, 2.3 Hz), 8.89(1H, s).

(Step 5)

HATU (245 mg, 0.64 mmol) was added to a solution ofN-(4-(tert-butyl)-3-fluorophenyl)-8-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxamide(200 mg, 0.54 mmol), 3-hydroxy-1,2-oxazole-5-carboxylic acid (72.8 mg,0.56 mmol) and DIEA (187 μL, 1.07 mmol) in DMF (2.6 mL) at roomtemperature, and the mixture was stirred at room temperature for 15 hr.To the reaction mixture was added water, and the mixture was extractedthree times with a mixed solvent of ethyl acetate/THF. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 30→100% ethylacetate/hexane), and the precipitate was washed with diethyl ether/IPEto give the title compound (70.0 mg, 0.145 mmol, 27.0%) as whitecrystals.

MS(API): Calculated 483.5. Found 484.1 (M+H).

¹H NMR (300 MHz, CDCl₃): δ 1.32 (9H, s), 3.73-4.23 (6H, m), 4.40-4.59(1H, m), 5.84-6.39 (1H, m), 6.49 (1H, s), 6.69-6.78 (2H, m), 6.89-6.98(1H, m), 7.11-7.22 (2H, m), 7.23-7.30 (2H, m), 7.36 (1H, d, J=8.7 Hz).

Example 36N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-4-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-carboxamide(Step 1)

To a solution of 1,3-difluoro-5-nitrobenzene (3 g, 18.86 mmol) in THF(60 mL) was added trimethylsilyl chloride (7.23 mL, 56.57 mmol) undernitrogen atmosphere at −78° C. To the reaction solution was added sodiumhexamethyldisilazide (19.85 mL, 37.71 mmol), and the mixture wasmaintained at −75° C. or below. The reaction solution was stirred for 1hr, and water and ethyl acetate were added thereto. The organic layerwas separated, and the aqueous layer was extracted with ethyl acetate.The organic layer was dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent; hexane) to give(2,6-difluoro-4-nitrophenyl)trimethylsilane (3.51 g, 15.18 mmol, 80%) asa colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 0.42 (9H, s), 7.61-7.71 (2H, m).

(Step 2)

A solution of (2,6-difluoro-4-nitrophenyl)trimethylsilane (3.5 g, 15.13mmol) and 10% palladium-carbon (350 mg, 0.16 mmol, 50% wet) in MeOH (70mL) was stirred under hydrogen atmosphere (1 atm) at room temperaturefor 5 hr. The catalyst was filtered off, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent; ethyl acetate/hexane) togive 3,5-difluoro-4-(trimethylsilyl)aniline (2.50 g, 12.42 mmol, 82%) asa pale yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 0.30 (9H, s), 3.88 (2H, brs), 5.99-6.16 (2H,m).

(Step 3)

T3P (1.909 mL, 3.21 mmol) was added to a solution of4-(tert-butoxycarbonyl)-8-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylicacid (692 mg, 2.14 mmol), 3,5-difluoro-4-(trimethylsilyl)aniline (431mg, 2.14 mmol), DIEA (1.864 mL, 10.70 mmol) and DMAP (288 mg, 2.35 mmol)in ethyl acetate (17 mL), and the mixture was stirred at 65° C. for 15hr. To the reaction mixture was added water, and the mixture wasextracted three times with ethyl acetate. The organic layer was washedwith 10% aqueous citric acid solution, aqueous sodium hydrogen carbonatesolution and brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 5→30% ethylacetate/hexane) to give tert-butyl5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-8-methoxy-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(924 mg, 1.824 mmol, 85%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.31 (9H, s), 1.47 (9H, s), 3.66-3.78 (1H,m), 3.81 (3H, s), 3.86-3.95 (2H, m), 4.33 (1H, brs), 5.38-5.98 (1H, m),6.65 (1H, d, J=2.3 Hz), 6.70 (1H, dd, J=8.3, 2.3 Hz), 6.95 (2H, d, J=8.7Hz), 7.19-7.25 (1H, m), 7.46-7.97 (1H, m).

(Step 4)

Cooled TFA (10 mL, 134.6 mmol) was added to tert-butyl5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-8-methoxy-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (919 mg, 1.81 mmol), and the mixture was stirred atroom temperature for 2 min. The reaction mixture was added to ice andaqueous sodium hydrogen carbonate solution, and potassium carbonate wasadded thereto until the pH of the mixture became 8. Then, the mixturewas extracted three times with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The precipitate was washed withhexane to giveN-(3,5-difluoro-4-(trimethylsilyl)phenyl)-8-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxamide(652 mg, 1.604 mmol, 88%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 0.34 (9H, s), 1.74 (1H, brs), 3.13-3.29 (2H,m), 3.80 (3H, s), 3.96-4.13 (2H, m), 4.69 (1H, s), 6.62-6.67 (2H, m),7.08-7.16 (2H, m), 7.17-7.21 (1H, m), 9.16 (1H, s).

(Step 5)

HATU (245 mg, 0.64 mmol) was added to a solution ofN-(3,5-difluoro-4-(trimethylsilyl)phenyl)-8-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxamide(218 mg, 0.54 mmol), 3-hydroxy-1,2-oxazole-5-carboxylic acid (72.7 mg,0.56 mmol) and DIEA (187 μL, 1.07 mmol) in DMF (2.6 mL) at roomtemperature, and the mixture was stirred at room temperature for 15 hr.To the reaction mixture was added water, and the mixture was extractedthree times with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 30→100% ethyl acetate/hexane), and theprecipitate was washed with IPE/hexane to give the title compound (114.5mg, 0.221 mmol, 41.3%) as white crystals.

MS(API): Calculated 517.6. Found 518.1 (M+H).

¹H NMR (300 MHz, CDCl₃): δ 0.31 (9H, s), 3.73-3.88 (4H, m), 3.91-4.17(3H, m), 4.40-4.53 (1H, m), 5.82-6.35 (1H, m), 6.51 (1H, s), 6.70 (1H,d), 6.75 (1H, dd, J=8.3, 2.3 Hz), 6.85-6.95 (2H, m), 7.13-7.23 (1H, m),7.32-7.38 (1H, m).

Example 37 ethyl2-(2-fluoro-4-(((2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)carbonyl)amino)phenyl)-2-methylpropanoate(Step 1)

Diethyl malonate (20.14 g, 125.71 mmol) was added to a suspension ofsodium hydride (60% oil, 5.28 g, 132.00 mmol) in DMF (100 mL) at 0° C.,and the mixture was stirred at 0° C. for 30 min. Then,1,2-difluoro-4-nitrobenzene (10 g, 62.86 mmol) was slowly added thereto,and the mixture was stirred overnight at 70° C. To the reaction mixturewere added aqueous ammonium chloride and ethyl acetate, and the organiclayer was separated. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→40% ethyl acetate/hexane), and thensilica gel column chromatography (NH, solvent gradient; 0→920% ethylacetate/hexane) to give diethyl 2-(2-fluoro-4-nitrophenyl)malonate(16.20 g, 54.1 mmol, 86%) as a yellow oil.

¹H NMR (300 MHz, DMSO-d₆): δ 1.13-1.24 (6H, m), 4.19 (4H, q, J=7.2 Hz),5.36 (1H, s), 7.67-7.82 (1H, m), 8.16 (2H, ddd, J=16.1, 9.1, 2.5 Hz).

(Step 2)

Lithium chloride (3.44 g, 81.20 mmol) was added to a solution of diethyl2-(2-fluoro-4-nitrophenyl)malonate (16.2 g, 54.14 mmol) in a mixedsolvent of water (0.975 mL, 54.14 mmol) and DMSO (20 mL), and themixture was stirred overnight at 120° C. To the reaction mixture wereadded 0.1N hydrochloric acid and ethyl acetate, and the organic layerwas separated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (NH, solvent gradient; 0→20% ethyl acetate/hexane) togive ethyl 2-(2-fluoro-4-nitrophenyl)acetate (7.38 g, 32.5 mmol, 60.0%)as a yellow oil.

¹H NMR (300 MHz, DMSO-d₆): δ 1.19 (3H, t, J=7.2 Hz), 3.91 (2H, d, J=1.1Hz), 4.12 (2H, q, J=7.2 Hz), 7.62-7.76 (1H, m), 8.04-8.17 (2H, m).

(Step 3)

To a solution of ethyl 2-(2-fluoro-4-nitrophenyl)acetate (7.38 g, 32.48mmol) and iodomethane (8.12 mL, 129.94 mmol) in DMF (150 mL) was addedsodium hydride (60% oil, 3.25 g, 81.21 mmol) at 0° C., and the mixturewas stirred at 0° C. for 4 hr. To the reaction mixture were addedaqueous ammonium chloride solution and ethyl acetate, and the organiclayer was separated. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 5→20% ethyl acetate/hexane) to giveethyl 2-(2-fluoro-4-nitrophenyl)-2-methylpropanoate (7.22 g, 28.3 mmol,873) as yellow crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 1.11 (3H, t, J=7.0 Hz), 1.53 (6H, s), 4.09(2H, q, J=6.9 Hz), 7.68-7.81 (1H, m), 8.03-8.18 (2H, m).

(Step 4)

A solution of ethyl 2-(2-fluoro-4-nitrophenyl)-2-methylpropanoate (2 g,7.84 mmol) and 10% palladium-carbon (0.834 g, 0.39 mmol, 50% wet) inEtOH (50 mL) was stirred overnight under hydrogen atmosphere (1 atm) atroom temperature. The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure to give ethyl2-(4-amino-2-fluorophenyl)-2-methylpropanoate (1.770 g, 7.86 mmol, 100%)as a yellow oil.

¹H NMR (300 MHz, DMSO-dr): δ 1.01-1.18 (3H, m), 1.38 (6H, s), 4.03 (2H,q, J=7.2 Hz), 5.26 (2H, s), 6.17-6.39 (2H, m), 6.98 (1H, dd, J=9.3, 8.5Hz).

(Step 5)

T3P (7.01 mL, 11.79 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (2.415 g, 7.86 mmol), ethyl2-(4-amino-2-fluorophenyl)-2-methylpropanoate (1.77 g, 7.86 mmol), DIEA(6.86 mL, 39.29 mmol) and DMAP (1.056 g, 8.64 mmol) in ethyl acetate(100 mL), and the mixture was stirred at 70° C. for 15 hr. To thereaction mixture was added water, and the mixture was extracted twicewith ethyl acetate. The organic layer was washed with aqueous sodiumhydrogen carbonate solution and brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 0→30% ethyl acetate/hexane) to give tert-butyl1-((4-(1-ethoxy-2-methyl-1-oxopropan-2-yl)-3-fluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(2.78 g, 5.40 mmol, 68.8%) as a pale yellow solid.

¹H NMR (300 MHz, DMSO-d₆): δ 1.08 (3H, t, J=7.0 Hz), 1.35 (6H, s), 1.44(9H, s), 2.66-2.82 (1H, m), 3.05 (1H, brs), 3.35-3.50 (1H, m), 3.72 (3H,s), 3.87-4.01 (1H, m), 4.00-4.11 (2H, m), 5.21-5.50 (1H, m), 6.69-6.91(2H, m), 7.22-7.39 (2H, m), 7.40-7.57 (2H, m), 10.35-10.62 (1H, m).

(Step 6)

4N hydrogen chloride/MeOH (5 mL, 20.00 mmol) was added to a solution oftert-butyl1-((4-(1-ethoxy-2-methyl-1-oxopropan-2-yl)-3-fluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.74 g, 3.38 mmol) in MeOH (5 mL), and the mixture was stirredovernight at room temperature. The reaction mixture was concentratedunder reduced pressure to give ethyl2-(2-fluoro-4-(6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide)phenyl)-2-methylpropanoatehydrochloride (1.600 g, 3.55 mmol, 105%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 1.10 (3H, t, J=7.0 Hz), 1.47 (6H, s),2.87-3.04 (1H, m), 3.05-3.20 (1H, m), 3.43 (1H, brs), 3.62-3.85 (4H, m),4.00-4.14 (2H, m), 5.24 (1H, brs), 6.84-6.94 (2H, m), 7.36 (1H, d, J=9.4Hz), 7.40-7.49 (2H, m), 7.51-7.63 (1H, m), 9.37 (1H, brs), 10.09 (1H,brs), 11.51 (1H, s).

(Step 7)

HATU (1.096 g, 2.88 mmol) was added to a solution of DIEA (1.162 mL,6.65 mmol), 3-hydroxy-1,2-oxazole-5-carboxylic acid (0.372 g, 2.88 mmol)and ethyl2-(2-fluoro-4-(6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide)phenyl)-2-methylpropanoatehydrochloride (1 g, 2.22 mmol) in DMF (15 mL) at room temperature, andthe mixture was stirred at room temperature for 5 hr. To the reactionmixture was added aqueous sodium hydrogen carbonate solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 50→100% ethylacetate/hexane, 0→10% MeOH/ethyl acetate) to give the title compound(0.412 g, 0.784 mmol, 35.4%) as a white solid.

MS(API): Calculated 525.5. Found 524.1 (M−H).

¹H NMR (300 MHz, DMSO-d): δ 1.08 (3H, t, J=7.0 Hz), 1.43 (6H, s),2.78-2.97 (1H, m), 3.05-3.26 (1H, m), 3.62-3.86 (4H, m), 3.96-4.10 (2H,m), 4.11-4.23 (1H, m), 5.69 (1H, s), 6.59 (1H, s), 6.77-6.97 (2H, m),7.21-7.40 (2H, m), 7.43-7.60 (2H, m), 10.73 (1H, s), 11.76 (1H, s).

Example 38N-(4-tert-butyl-3-fluorophenyl)-6-(1H-indazol-1-ylacetyl)-1-methyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-5-carboxamide(Step 1)

Iodomethane (1.947 mL, 31.27 mmol) was added to a solution of 5-ethyl6-tert-butyl2-hydroxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (5.04 g,15.63 mmol) and cesium carbonate (6.62 g, 20.33 mmol) in DMF (35 mL),and the mixture was stirred at room temperature for 3.5 hr. To thereaction mixture was added water, and the mixture was extracted threetimes with a mixed solvent of ethyl acetate/THF. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 10→100% ethylacetate/hexane) to give 5-ethyl 6-tert-butyl1-methyl-2-oxo-1,2,7,8-tetrahydro-1,6-naphthyridine-5,6(5H)-dicarboxylate(3.60 g, 10.70 mmol, 68.5%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.25-1.33 (3H, m), 1.44-1.52 (9H, m),2.64-2.88 (2H, m), 3.37-3.59 (4H, m), 4.17-4.37 (3H, m), 5.16-5.39 (1H,m), 6.52 (1H, d, J=9.4 Hz), 7.45-7.53 (1H, m).

(Step 2)

2N Aqueous lithium hydroxide solution (32.1 mL, 64.21 mmol) was added toa solution of 5-ethyl 6-tert-butyl1-methyl-2-oxo-1,2,7,8-tetrahydro-1,6-naphthyridine-5,6(5H)-dicarboxylate(3.60 g, 10.70 mmol) in a mixed solvent of EtOH (15 mL) and THF (15 mL),and the mixture was stirred at room temperature for 2 hr. To thereaction mixture was added ice-water, and 2N hydrochloric acid was addedthereto until the pH of the mixture became 4. Then, the mixture wasextracted three times with a mixed solvent of ethyl acetate/THF. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The precipitatewas washed with IPE/hexane to give6-(tert-butoxycarbonyl)-1-methyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-5-carboxylicacid (2.82 g, 9.15 mmol, 85%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 1.36-1.47 (9H, m), 2.75-2.86 (2H, m),3.15-3.27 (1H, m), 3.39 (3H, s), 4.03-4.14 (1H, m), 5.09-5.23 (1H, m),6.34 (1H, d, J=9.4 Hz), 7.50 (1H, d, J=9.4 Hz), 13.17 (1H, brs).

(Step 3)

T3P (1.047 mL, 1.76 mmol) was added to a solution of6-(tert-butoxycarbonyl)-1-methyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-5-carboxylicacid (362 mg, 1.17 mmol), 4-(tert-butyl)-3-fluoroaniline (196 mg, 1.17mmol), DIEA (1.023 mL, 5.87 mmol) and DMAP (158 mg, 1.29 mmol) in ethylacetate (9.5 mL), and the mixture was stirred at 65° C. for 15 hr. Tothe reaction mixture was added water, and the mixture was extractedthree times with ethyl acetate. The organic layer was washed with 10%aqueous citric acid solution, aqueous sodium hydrogen carbonate solutionand brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 0→10% MeOH/ethylacetate) to give tert-butyl5-((4-(tert-butyl)-3-fluorophenyl)carbamoyl)-1-methyl-2-oxo-1,2,7,8-tetrahydro-1,6-naphthyridine-6(5H)-carboxylate(494 mg, 1.080 mmol, 92%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.35 (9H, s), 1.54 (9H, s), 2.67-2.90 (2H,m), 3.22-3.34 (1H, m), 3.52 (3H, s), 4.23 (1H, dd, J=13.6, 4.9 Hz), 5.44(1H, brs), 6.56 (1H, d, J=9.4 Hz), 7.06 (1H, dd, J=8.3, 2.3 Hz),7.13-7.25 (2H, m), 7.38 (1H, dd, J=14.4, 2.3 Hz), 8.79 (1H, brs).

(Step 4)

TFA (5.5 mL, 74.0 mmol) was added to tert-butyl5-((4-(tert-butyl)-3-fluorophenyl)carbamoyl)-1-methyl-2-oxo-1,2,7,8-tetrahydro-1,6-naphthyridine-6(5H)-carboxylate(491 mg, 1.07 mmol), and the mixture was stirred at room temperature for20 min. The reaction mixture was added to ice and aqueous sodiumhydrogen carbonate solution, and potassium carbonate was added theretountil the pH of the mixture became 8. Then, the mixture was extractedthree times with a mixed solvent of ethyl acetate/THF. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The precipitate was washed withIPE/hexane to giveN-(4-(tert-butyl)-3-fluorophenyl)-1-methyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-5-carboxamide(325 mg, 0.909 mmol, 85%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 1.35 (9H, s), 2.13 (1H, brs), 2.60-2.77 (2H,m), 3.06-3.17 (1H, m), 3.22-3.31 (1H, m), 3.49 (3H, s), 4.41 (1H, s),6.52 (1H, d, J=9.4 Hz), 7.12 (1H, dd), 7.21 (1H, t), 7.42 (1H, dd,J=14.4, 2.3 Hz), 7.58 (1H, d, J=9.4 Hz), 9.25 (1H, s).

(Step 5)

HATU (102 mg, 0.27 mmol) was added to a solution ofN-(4-(tert-butyl)-3-fluorophenyl)-1-methyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-5-carboxamide(80 mg, 0.22 mmol), 2-(1H-indazol-1-yl)acetic acid (41.4 mg, 0.24 mmol)and DIEA (78 μL, 0.45 mmol) in DMF (1.2 mL) at room temperature, and themixture was stirred at room temperature for 15 hr. To the reactionmixture was added water, and the mixture was extracted three times witha mixed solvent of ethyl acetate/THF. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The precipitate was washed with IPE/hexane togive the title compound (93.8 mg, 0.182 mmol, 81%) as white crystals.

MS(API): Calculated 515.6. Found 516.3 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ 1.29 (9H, s), 3.01-3.08 (2H, m), 3.46 (3H,s), 4.14 (2H, t, J=5.7 Hz), 5.54 (1H, s), 5.57-5.73 (2H, m), 6.38 (1H,d, J=9.4 Hz), 7.13 (1H, t), 7.21 (1H, dd), 7.26 (1H, t), 7.35 (1H, t,J=7.7 Hz), 7.42-7.46 (1H, m), 7.48 (1H, s), 7.56 (1H, d, J=8.3 Hz), 7.76(1H, d, J=7.9 Hz), 8.08 (1H, s), 10.48 (1H, s).

Example 39N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-(1H-indazol-1-ylacetyl)-1-methyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-5-carboxamide

The title compound was synthesized by the reaction and purification inthe same manner as in Example 38.

Example 40(1R)—N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-(2H-tetrazol-5-ylacetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

The title compound was synthesized by the reaction and purification inthe same manner as in Examples 1 and 25.

Example 41N-(4-tert-butyl-3-fluorophenyl)-6-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(Step 1)

n-BuLi (84 mL, 133.98 mmol) was slowly added to a solution of2-methoxy-6-methylpyridine (15.00 g, 121.80 mmol) in THF (200 mL) underargon gas atmosphere at −78° C., and the mixture was stirred at −78° C.for 25 min. Then, paraformaldehyde (14.63 g, 487.20 mmol) was addedthereto at −78° C., and the mixture was stirred at room temperature for4 hr. To the reaction mixture were added ice water and sodium chloride,and the mixture was extracted four times with a mixed solvent of ethylacetate/THF. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 5→40% ethyl acetate/hexane) to give2-(6-methoxypyridin-2-yl)ethanol (7.93 g, 51.8 mmol, 42.5%) as acolorless oil.

(Step 2)

2.2M DEAD/toluene solution (30.6 mL, 67.22 mmol) was added to a solutionof 2-(6-methoxypyridin-2-yl)ethanol (7.92 g, 51.70 mmol), PPh₃ (17.63 g,67.22 mmol) and phthalimide (8.37 g, 56.87 mmol) in THF (120 mL) underargon gas atmosphere at 0° C., and the mixture was stirred at roomtemperature for 15 hr. To the reaction mixture was added water, and themixture was extracted three times with ethyl acetate. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 2→20% ethylacetate/hexane) to give2-(2-(6-methoxypyridin-2-yl)ethyl)isoindoline-1,3-dione (12.45 g, 44.1mmol, 85%) as a colorless oil.

(Step 3)

Hydrazine monohydrate (10.95 mL, 225.83 mmol) was added to a solution of2-(2-(6-methoxypyridin-2-yl)ethyl)isoindoline-1,3-dione (12.75 g, 45.17mmol) in EtOH (125 mL), and the mixture was heated under reflux for 1hr. The reaction mixture was cooled, and the insoluble substance wasremoved by filtration. The filtrate was concentrated under reducedpressure, and the obtained residue was purified by silica gel columnchromatography (NH, solvent gradient; 30→100% ethyl acetate/hexane) togive 2-(6-methoxypyridin-2-yl)ethanamine (6.53 g, 42.9 mmol, 95-) as acolorless oil.

(Step 4)

A solution of 2-(6-methoxypyridin-2-yl)ethanamine (6.53 g, 42.91 mmol),4N hydrogen chloride/CPME solution (23.60 mL, 94.39 mmol) and 47% ethylglyoxylate/toluene solution (27.1 mL, 128.72 mmol) in EtOH (75 mL) washeated under reflux for 20 hr. The reaction mixture was concentratedunder reduced pressure, and the precipitate was washed with EtOH/diethylether to give ethyl2-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylatehydrochloride (8.89 g, 34.4 mmol, 80%) as a white solid.

(Step 5)

Boc₂O (7.87 g, 36.08 mmol) was added to a solution of ethyl2-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylatehydrochloride (8.89 g, 34.36 mmol) and TEA (5.03 mL, 36.08 mmol) in amixed solvent of THF (95 mL) and water (35 mL), and the mixture wasstirred at room temperature for 15 hr. To the reaction mixture was addedbrine, and the mixture was extracted three times with a mixed solvent ofethyl acetate/THF. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The precipitate was washed with IPE/hexane to give 5-ethyl6-tert-butyl2-hydroxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (6.85 g,21.25 mmol, 61.8%) as a white solid.

(Step 6)

Iodomethane (7.94 mL, 127.50 mmol) was added to a solution of 5-ethyl6-tert-butyl2-hydroxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (6.85 g,21.25 mmol) and silver(I) carbonate (7.62 g, 27.62 mmol) in THF (140mL), and the mixture was stirred at room temperature for 15 hr, and thenat 50° C. for 8 hr. The reaction mixture was cooled, and the insolublesubstance was removed by filtration. The filtrate was concentrated underreduced pressure, and the obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 5→30% ethyl acetate/hexane) togive 5-ethyl 6-tert-butyl2-methoxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (6.41 g,19.06 mmol, 90%) as a colorless oil.

(Step 7)

2N Aqueous lithium hydroxide solution (6.29 mL, 12.57 mmol) was added toa solution of 5-ethyl 6-tert-butyl2-methoxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (705 mg,2.10 mmol) in a mixed solvent of EtOH (3 mL) and THF (3 mL), and themixture was stirred at room temperature for 2 hr. To the reactionmixture was added ice water, and 2N hydrochloric acid was added theretountil the pH of the mixture became 4. Then, the mixture was extractedthree times with a mixed solvent of ethyl acetate/THF. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure to give6-(tert-butoxycarbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylicacid (643 mg, 2.085 mmol, 100%) as a white solid.

(Step 8)

T3P (1.227 mL, 2.06 mmol) was added to a solution of6-(tert-butoxycarbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylicacid (424 mg, 1.38 mmol), 4-(tert-butyl)-3-fluoroaniline (230 mg, 1.38mmol), DIEA (1.198 mL, 6.88 mmol) and DMAP (185 mg, 1.51 mmol) in ethylacetate (11 mL) at room temperature, and the mixture was stirred at 65°C. for 15 hr. To the reaction mixture was added water, and the mixturewas extracted three times with ethyl acetate. The organic layer waswashed with 10% aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The precipitate waswashed with hexane to give tert-butyl5-((4-(tert-butyl)-3-fluorophenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(471 mg, 1.029 mmol, 74.9%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 1.34 (9H, s), 1.53 (9H, s), 2.83-3.03 (2H,m), 3.47 (1H, brs), 3.92 (3H, s), 4.02-4.12 (1H, m), 5.59 (1H, brs),6.64 (1H, d, J=8.7 Hz), 7.05 (1H, d, J=8.7 Hz), 7.16-7.31 (2H, m), 7.39(1H, dd, J=14.4, 2.3 Hz), 7.48 (1H, brs).

(Step 9)

TFA (5.5 mL, 74.0 mmol) was added to tert-butyl5-((4-(tert-butyl)-3-fluorophenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(469 mg, 1.03 mmol), and the mixture was stirred at room temperature for20 min. The reaction mixture was added to ice and aqueous sodiumhydrogen carbonate solution, and potassium carbonate was added theretountil the pH of the mixture became 8. Then, the mixture was extractedthree times with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The precipitate was washed with IPE/hexane to giveN-(4-(tert-butyl)-3-fluorophenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(321 mg, 0.898 mmol, 88%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 1.34 (9H, d, J=0.8 Hz), 2.17 (1H, brs),2.74-2.85 (1H, m), 2.87-2.98 (1H, m), 3.13-3.29 (2H, m), 3.90 (3H, s),4.58 (1H, s), 6.60 (1H, d, J=8.3 Hz), 7.11 (1H, dd), 7.20 (1H, t), 7.44(1H, dd, J=14.4, 2.3 Hz), 7.83 (1H, d, J=8.7 Hz), 9.44 (1H, s).

(Step 10)

HATU (174 mg, 0.46 mmol) was added to a solution ofN-(4-(tert-butyl)-3-fluorophenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(136 mg, 0.38 mmol), 2-(3-hydroxy-1,2-oxazol-5-yl)acetic acid (57.2 mg,0.40 mmol) and DIEA (133 μL, 0.76 mmol) in DMF (1.9 mL) at roomtemperature, and the mixture was stirred for 15 hr. To the reactionmixture was added water, and the mixture was extracted three times withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 30→100% ethyl acetate/hexane), and theprecipitate was washed with diethyl ether/hexane to give the titlecompound (59.5 mg, 0.123 mmol, 32.4%) as white crystals.

MS(API): Calculated 482.5. Found 483.1 (M+H).

¹H NMR (300 MHz, CDCl₃): δ 1.31 (9H, s), 2.89-3.14 (2H, m), 3.87-3.99(7H, m), 5.95 (1H, s), 5.97 (1H, brs), 6.64 (1H, d, J=8.7 Hz), 6.98 (1H,d, J=8.3 Hz), 7.10-7.20 (2H, m), 7.32 (1H, dd, J=14.4, 1.9 Hz), 7.42(1H, d, J=8.3 Hz), 8.94 (1H, brs).

Example 42N-(4-(1-(ethylamino)-2-methyl-1-oxopropan-2-yl)-3-fluorophenyl)-6-methoxy-2-propionyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

The title compound was synthesized by the reaction and purification inthe same manner as in Examples 1 and 25.

Example 43(1R)—N-(4-tert-butyl-3,5-difluorophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

tert-Butyl1-((4-(tert-butyl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(2.080 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((4-(tert-butyl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(765 mg, >99.9% ee) as a white solid.

purification condition by chiral column chromatography

column: CHIRALPAK AD (AF003) 50 mmID×500 mmL

solvent: hexane/EtOH=850/150

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 2)

4M Hydrogen chloride/ethyl acetate (5 mL, 20.00 mmol) was added totert-butyl(R)-1-((4-(tert-butyl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(765 mg, 1.61 mmol), and the mixture was stirred overnight at roomtemperature. The reaction mixture was concentrated under reducedpressure, and the precipitate was washed with ethyl acetate/hexane togive(R)—N-(4-(tert-butyl)-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (550 mg, 1.339 mmol, 83%) as a white solid.

¹H NMR (300 MHz, DMSO-d): δ 1.41 (9H, t, J=2.1 Hz), 2.87-3.03 (1H, m),3.04-3.19 (1H, m), 3.36-3.48 (1H, m), 3.62-3.73 (1H, m), 3.75 (3H, s),5.20 (1H, s), 6.70-7.02 (2H, m), 7.17-7.48 (3H, m), 8.87-10.47 (2H, m),11.59 (1H, s).

(Step 3)

WSC (70.0 mg, 0.37 mmol) was added to a solution of DIEA (0.128 mL, 0.73mmol), HOBt (44.7 mg, 0.29 mmol), 2-(3-hydroxy-1,2-oxazol-5-yl)aceticacid (38.3 mg, 0.27 mmol) and(R)—N-(4-(tert-butyl)-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (100 mg, 0.24 mmol) in DMF (5 mL) at room temperature, andthe mixture was stirred at room temperature for 5 hr. To the reactionmixture was added aqueous sodium hydrogen carbonate solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 30→100% ethylacetate/hexane) to give the title compound (61.0 mg, 0.122 mmol, 50.2%)as white crystals.

MS(API): Calculated 499.5. Found 497.8 (M−H).

¹H NMR (300 MHz, DMSO-d): δ 1.38 (9H, s), 2.69-2.90 (1H, m), 3.03-3.18(1H, m), 3.49-3.62 (1H, m), 3.73 (3H, s), 3.88-4.16 (3H, m), 5.62 (1H,s), 5.90 (1H, s), 6.72-6.96 (2H, m), 7.18 (2H, d, J=13.2 Hz), 7.47 (1H,d, J=9.1 Hz), 10.69 (1H, s), 11.17 (1H, brs).

[α]_(D) ²⁵ +5.4 (c 0.2550, MeOH)

Example 45(1R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

tert-Butyl1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.54 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(562 mg, >99.9% ee) as a white solid.

purification condition by chiral column chromatography

column: CHIRALCEL OD (NL001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 2)

To a solution of tert-butyl(R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(750 mg, 1.60 mmol) in ethyl acetate (5.0 mL) was added 4M hydrogenchloride/ethyl acetate (7.0 mL, 28.00 mmol), and the mixture was stirredovernight at room temperature. The precipitate was collected byfiltration, and washed with ethyl acetate to give(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (528.4 mg, 1.305 mmol, 82%) as white crystals.

(Step 3)

To a solution of(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (50 mg, 0.12 mmol), DIEA (0.042 mL, 0.25 mmol) and2-(3-hydroxy-1,2-oxazol-5-yl)acetic acid (19.44 mg, 0.14 mmol) in DMF(2.0 mL) was added HATU (56.3 mg, 0.15 mmol), and the mixture wasstirred at room temperature for 2 hr. To the reaction mixture was addedwater, and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 0→50%ethyl acetate/hexane), and crystallized from ethyl acetate/hexane togive the title compound (32.5 mg, 0.066 mmol, 53.3%) as white crystals.

MS(API): Calculated 493.5. Found 492.1 (M−H).

¹H NMR (300 MHz, DMSO-d): δ 1.28 (6H, d, J=1.9 Hz), 1.86 (2H, t, J=7.2Hz), 2.72-2.91 (3H, m), 3.05-3.22 (1H, m), 3.52-3.68 (1H, m), 3.69-3.76(3H, m), 3.87-4.15 (3H, m), 5.61-5.71 (1H, m), 5.91 (1H, s), 6.74-6.89(2H, m), 7.11-7.26 (2H, m), 7.42-7.53 (1H, m), 10.46 (1H, s), 11.16 (1H,brs).

[α]_(D) ²⁵ +15.2 (c 0.2550, MeOH)

The compounds described in Examples 44 and 46 to 48 were synthesized bythe reaction and purification in the same manner as in Examples 1 and25.

Example 44(1R)—N-(4-tert-butyl-3-fluorophenyl)-2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamideExample 46N-(3-fluoro-4-(2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl)phenyl)-6-methoxy-2-propionyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamideExample 47(1R)—N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-propionyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamideExample 48(1R)—N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-(3,3,3-trifluoropropanoyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamideExample 49N-(4-tert-butyl-3-fluorophenyl)-4-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-carboxamide

The title compound was synthesized by the reaction and purification inthe same manner as in Example 5.

Example 50N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-4-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-carboxamide

HATU (480 mg, 1.26 mmol) was added to a solution ofN-(3,5-difluoro-4-(trimethylsilyl)phenyl)-8-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxamide(428 mg, 1.05 mmol), 2-(3-hydroxy-1,2-oxazol-5-yl)acetic acid (158 mg,1.11 mmol) and DIEA (367 μL, 2.11 mmol) in DMF (5.1 mL) at roomtemperature, and the mixture was stirred for 15 hr. To the reactionmixture was added water, and the mixture was extracted three times withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 20→90% ethyl acetate/hexane),and the precipitate was washed with IPE/hexane to give the titlecompound (141.7 mg, 0.267 mmol, 25.3%) as white crystals.

MS(API): Calculated 531.6. Found 530.0 (M−H).

¹H NMR (300 MHz, CDCl₃): δ 0.31 (9H, s), 3.83 (3H, s), 3.85-4.02 (5H,m), 4.31-4.40 (1H, m), 6.01 (1H, s), 6.41 (1H, s), 6.64 (1H, d, J=2.6Hz), 6.68-6.74 (2H, m), 6.87-6.95 (2H, m), 7.28-7.38 (2H, m).

The compounds described in Examples 51 to 53 were synthesized by thereaction and purification in the same manner as in Examples 1 and 25.

Example 51N-(4-tert-butyl-3-(difluoromethoxy)phenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamideExample 52N-(4-tert-butyl-3-(2,2-difluoroethoxy)phenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamideExample 53N-(4-tert-butyl-3-cyanophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamideExample 54N-(4-tert-butyl-3-fluorophenyl)-6-ethoxy-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

Iodoethane (7.12 mL, 88.37 mmol) was added to a solution of 1-ethyl2-tert-butyl 6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate(14.2 g, 44.19 mmol) and cesium carbonate (18.72 g, 57.44 mmol) in DMF(100 mL), and the mixture was stirred at room temperature for 2.5 hr. Tothe reaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reduced pressureto give 1-ethyl 2-tert-butyl6-ethoxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (13.0 g, 37.2mmol, 84%) as a colorless oil.

(Step 2)

2N Aqueous sodium hydroxide solution (55.8 mL, 111.61 mmol) was added toa solution of 1-ethyl 2-tert-butyl6-ethoxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (13.0 g, 37.20mmol) in a mixed solvent of EtOH (100 mL) and THF (100 mL), and themixture was stirred overnight at room temperature. To the reactionmixture was added ice water, and the mixture was washed with diethylether. 2N Hydrochloric acid was added thereto until the pH of themixture became 4. Then, the mixture was extracted with ethyl acetate.The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure to give2-(tert-butoxycarbonyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (3.56 g, 11.08 mmol, 29.8%) as a colorless oil.

(Step 3)

To a solution of 4-(tert-butyl)-3-fluoroaniline (500 mg, 2.99 mmol),2-(tert-butoxycarbonyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (1057 mg, 3.29 mmol), DMAP (402 mg, 3.29 mmol) and DIEA (2.61 mL,14.95 mmol) in ethyl acetate (10 mL) was added T3P (3.52 mL, 5.98 mmol),and the mixture was stirred at 80° C. for 2 hr. To the reaction mixturewas added water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solvent; ethylacetate/hexane), and crystallized from diethyl ether/hexane to givetert-butyl1-((4-(tert-butyl)-3-fluorophenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(689.3 mg, 1.465 mmol, 49.0%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.33 (9H, d, J=0.8 Hz), 1.40 (3H, t, J=6.8Hz), 1.52 (9H, s), 2.75-2.97 (2H, m), 3.53-3.78 (2H, m), 4.02 (2H, q,J=6.8 Hz), 5.59 (1H, brs), 6.67-6.83 (2H, m), 7.03 (1H, d, J=7.9 Hz),7.12-7.22 (2H, m), 7.32-7.43 (1H, m), 8.87 (1H, brs).

(Step 4)

To a solution of tert-butyl1-((4-(tert-butyl)-3-fluorophenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(680 mg, 1.45 mmol) in ethyl acetate (7.0 mL) was added 4N hydrogenchloride/ethyl acetate (7.0 mL, 28.00 mmol), and the mixture was stirredat room temperature for 5 hr. The precipitate was collected byfiltration, and washed with ethyl acetate to giveN-(4-(tert-butyl)-3-fluorophenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (506.2 mg, 1.244 mmol, 86%) as white crystals.

¹H NMR (300 MHz, DMSO-d): δ 1.27-1.37 (12H, m), 2.88-3.19 (2H, m),3.38-3.48 (1H, m), 3.70 (1H, dt, J=12.2, 5.8 Hz), 4.01 (2H, q, J=6.8Hz), 5.25 (1H, s), 6.75-6.94 (2H, m), 7.26-7.44 (3H, m), 7.47-7.61 (1H,m), 9.37 (1H, brs), 10.20 (1H, brs), 11.51 (1H, s).

(Step 5)

To a solution ofN-(4-(tert-butyl)-3-fluorophenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (500 mg, 1.23 mmol), DIEA (0.420 mL, 2.46 mmol) and2-(3-hydroxy-1,2-oxazol-5-yl)acetic acid (211 mg, 1.47 mmol) in DMF (10mL) was added HATU (561 mg, 1.47 mmol) at room temperature, and themixture was stirred for 5 hr. To the reaction mixture was added water,and the mixture was extracted with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 0→50% ethylacetate/hexane), and crystallized from ethyl acetate/hexane to give thetitle compound (444.0 mg, 0.896 mmol, 72.9%) as white crystals.

MS(API): Calculated 495.5. Found 494.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ 1.24-1.34 (12H, m), 2.70-2.88 (1H, m),3.06-3.20 (1H, m), 3.52-3.67 (1H, m), 3.91-4.14 (5H, m), 5.58-5.70 (1H,m), 5.82-5.94 (1H, m), 6.75-6.86 (2H, m), 7.15-7.29 (2H, m), 7.38-7.50(2H, m), 10.54 (1H, s), 11.14 (1H, brs).

Example 556-ethoxy-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

To a solution of 7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine (365mg, 2.04 mmol),2-(tert-butoxycarbonyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (720 mg, 2.24 mmol), DMAP (274 mg, 2.24 mmol) and DIEA (1.778 mL,10.18 mmol) in ethyl acetate (10 mL) was added T3P (2.396 mL, 4.07mmol), and the mixture was stirred at 80° C. for 2 hr. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent; ethyl acetate/hexane), and washed with diethylether/hexane to give tert-butyl6-ethoxy-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(482.9 mg, 1.001 mmol, 49.1%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 1.33 (6H, s), 1.40 (3H, t, J=7.0 Hz), 1.51(9H, s), 1.90 (2H, t, J=7.4 Hz), 2.79-2.93 (4H, m), 3.48-3.78 (2H, m),4.02 (2H, q, J=7.0 Hz), 5.54 (1H, brs), 6.66-6.83 (2H, m), 6.94-7.21(3H, m), 8.76 (1H, brs).

(Step 2)

To a solution of tert-butyl6-ethoxy-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(480 mg, 0.99 mmol) in ethyl acetate (5.0 mL) was added 4N hydrogenchloride/ethyl acetate (5.0 mL, 20.00 mmol), and the mixture was stirredat room temperature for 5 hr. The precipitate was collected byfiltration, and washed with ethyl acetate to give6-ethoxy-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (360.5 mg, 0.861 mmol, 87%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 1.26-1.36 (9H, m), 1.90 (2H, t, J=7.4 Hz),2.85-3.17 (4H, m), 3.36-3.45 (1H, m), 3.56-3.77 (1H, m), 4.01 (2H, q,J=7.2 Hz), 5.27 (1H, s), 6.81-6.90 (2H, m), 7.26-7.40 (3H, m), 9.37 (1H,brs), 10.25 (1H, brs), 11.51 (1H, s).

(Step 3)

To a solution of6-ethoxy-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (350 mg, 0.84 mmol), DIEA (0.286 mL, 1.67 mmol) and2-(3-hydroxy-1,2-oxazol-5-yl)acetic acid (143 mg, 1.00 mmol) in DMF (7.0mL) was added HATU (381 mg, 1.00 mmol), and the mixture was stirred atroom temperature for 5 hr. To the reaction mixture was added water, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 00→50% ethylacetate/hexane), and crystallized from ethyl acetate/hexane to give thetitle compound (225.1 mg, 0.444 mmol, 53.1%) as white crystals.

MS(API): Calculated 507.6. Found 506.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ 1.24-1.34 (9H, m), 1.86 (2H, t, J=7.4 Hz),2.71-2.91 (3H, m), 3.05-3.18 (1H, m), 3.51-3.67 (1H, m), 3.95-4.11 (5H,m), 5.63-5.69 (1H, m), 5.84-5.93 (1H, m), 6.76-6.86 (2H, m), 7.13-7.27(2H, m), 7.40-7.51 (1H, m), 10.42-10.52 (1H, m), 11.14 (1H, brs).

Example 56(5R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-4-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-carboxamide

N-(3,5-Difluoro-4-(trimethylsilyl)phenyl)-4-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-carboxamide(116.7 mg) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give the titlecompound (48.6 mg, >99.9% ee) as a white solid.

MS(API): Calculated 531.6. Found 532.1 (M+H).

purification condition by chiral column chromatography

column: CHIRALPAK IA (QK001) 50 mmID×500 mmL

solvent: hexane/EtOH=500/500

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

The compounds described in Examples 57 to 60 were synthesized by thereaction and purification in the same manner as in Examples 5 and 56.

Example 57(5S)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-4-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-carboxamideExample 58(5R)—N-(4-tert-butyl-3,5-difluorophenyl)-4-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-carboxamideExample 59(5S)—N-(4-tert-butyl-3,5-difluorophenyl)-4-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-carboxamideExample 60(5R)—N-(4-tert-butyl-3,5-difluorophenyl)-4-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-carboxamide

The compounds described in Examples 61 and 62 were synthesized by thereaction and purification in the same manner as in Examples 1 and 25.

Example 61N-(4-(1-(cyclopropylamino)-2-methyl-1-oxopropan-2-yl)-3-fluorophenyl)-6-methoxy-2-(3,3,3-trifluoropropanoyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamideExample 62N-(3-fluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-6-methoxy-2-(3,3,3-trifluoropropanoyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamideExample 63(1R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-(3-(3-hydroxy-1,2-oxazol-5-yl)propanoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

To a solution of(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(70 mg, 0.19 mmol), DIEA (0.065 mL, 0.38 mmol) and3-(3-hydroxy-1,2-oxazol-5-yl)propanoic acid (35.8 mg, 0.23 mmol) in DMF(2.0 mL) was added HATU (87 mg, 0.23 mmol) at 0° C., and the mixture wasstirred at room temperature for 2 hr. To the reaction mixture was addedwater, and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 0→50%ethyl acetate/hexane) to give the title compound (37.9 mg, 0.075 mmol,39.3%) as a white solid.

MS(API): Calculated 507.6. Found 508.2 (M+H).

¹H NMR (300 MHz, DMSO-d): δ 1.28 (6H, d, J=1.1 Hz), 1.81-1.91 (2H, m),2.73-2.98 (7H, m), 3.06-3.21 (1H, m), 3.49-3.62 (1H, m), 3.73 (3H, s),4.02-4.12 (1H, m), 5.59-5.81 (2H, m), 6.76-6.87 (2H, m), 7.15 (1H, s),7.22 (1H, d, J=12.5 Hz), 7.47 (1H, d, J=8.7 Hz), 10.38 (1H, s), 11.01(1H, brs).

Example 65(1R)—N-(4-tert-butyl-3-cyanophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

To a mixture of 1-(tert-butyl)-4-nitrobenzene (1 g, 5.58 mmol) in conc.sulfuric acid (5 mL) was added silver(I) sulfate (1.11 g, 3.57 mmol).Then, bromine (0.286 mL, 5.58 mmol) was slowly added thereto at 0° C.,and the mixture was stirred at room temperature for 3 hr. The reactionmixture was added to ice-water, and the mixture was extracted with ethylacetate. The organic layer was washed with aqueous sodium hydrogencarbonate solution, and the insoluble substance was removed byfiltration. The filtrate was dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure to give2-bromo-1-(tert-butyl)-4-nitrobenzene (1.4 g, 5.42 mmol, 97%) as ayellow oil.

¹H NMR (300 MHz, CDCl₃): δ 1.55 (9H, s), 7.61 (1H, d, J=9.1 Hz),8.04-8.11 (1H, m), 8.45 (1H, d, J=2.6 Hz).

(Step 2)

A solution of 2-bromo-1-(tert-butyl)-4-nitrobenzene (191 mg, 0.74 mmol),zinc cyanide (69.3 mg, 0.59 mmol) and Pd(Ph₃)₄ (42.8 mg, 0.04 mmol) inDMF (1 mL) was stirred under microwave irradiation at 200° C. for 3 hr.Similarly, a solution of 2-bromo-1-(tert-butyl)-4-nitrobenzene (1.2 g,4.65 mmol), zinc cyanide (437 mg, 3.72 mmol) and Pd(Ph₃)₄ (0.269 g, 0.23mmol) in DMF (4.65 mL) was stirred under microwave irradiation at 200°C. for 3 hr. To these reaction mixtures was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 0→40% ethyl acetate/hexane) togive 5-nitro-2-(tert-butyl)benzonitrile (223 mg, 1.280 mmol, 27.5%).

¹H NMR (300 MHz, CDCl₃): δ 1.58 (9H, s), 7.67 (1H, d, J=8.3 Hz), 8.05(1H, dd, J=8.7, 2.3 Hz), 8.24 (1H, d, J=2.3 Hz).

(Step 3)

A solution of 5-nitro-2-(tert-butyl)benzonitrile (3.81 g, 18.66 mmol),10% palladium-carbon (1.985 g, 0.94 mmol, 50% wet) and ammonium formate(3.53 g, 55.97 mmol) in EtOH (100 mL) was stirred under nitrogenatmosphere at 80° C. for 1.5 hr. The catalyst was removed by filtration,and the filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 3→50% ethyl acetate/hexane), and then silica gel columnchromatography (NH, solvent gradient; 3→60% ethyl acetate/hexane) togive 5-amino-2-(tert-butyl)benzonitrile (2.9 g, 16.64 mmol, 89%) as acolorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.46 (9H, s), 3.72 (2H, brs), 6.78 (1H, dd,J=8.7, 2.6 Hz), 6.95 (1H, d, J=3.0 Hz), 7.23 (1H, d, J=8.3 Hz).

(Step 4)

T3P (6.66 mL, 11.19 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (2.52 g, 8.21 mmol), 5-amino-2-(tert-butyl)benzonitrile (1.3 g,7.46 mmol), DIEA (6.50 mL, 37.30 mmol) and DMAP (1.003 g, 8.21 mmol) inethyl acetate (95 mL), and the mixture was stirred at 70° C. for 3 hr.To the reaction mixture was added water, and the mixture was extractedthree times with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent; ethyl acetate/hexane), and crystallized fromdiethyl ether/hexane, and washed to give tert-butyl1-((4-(tert-butyl)-3-cyanophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(2.23 g, 4.81 mmol, 64.5%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 1.47 (9H, s), 1.53 (9H, s), 2.75-3.03 (2H,m), 3.58-3.76 (2H, m), 3.80 (3H, s), 5.61 (1H, brs), 6.68-6.85 (2H, m),7.18-7.26 (1H, m), 731-7.39 (1H, m), 7.54-7.61 (1H, m), 7.86 (1H, d,J=2.3 Hz), 9.14 (1H, brs).

(Step 5)

tert-Butyl1-((4-(tert-butyl)-3-cyanophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(2.23 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((4-(tert-butyl)-3-cyanophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.90 g, >99.9% ee) as a white solid.

purification condition by chiral column chromatography

column: CHIRALPAK OD (NL001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 6)

To a solution of tert-butyl(R)-1-((4-(tert-butyl)-3-cyanophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(870 mg, 1.88 mmol) in ethyl acetate (8.0 mL) was added 4M hydrogenchloride/ethyl acetate solution (8.0 mL, 32.00 mmol), and the mixturewas stirred overnight at room temperature. The reaction mixture wasconcentrated under reduced pressure, and to the obtained residue wereadded ethyl acetate and aqueous sodium hydrogen carbonate solution. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure to give(R)—N-(4-(tert-butyl)-3-cyanophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(551.4 mg, 1.517 mmol, 81%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.48 (9H, s), 2.67-2.95 (2H, m), 3.09-3.19(2H, m), 3.78 (3H, s), 4.64 (1H, s), 6.64 (1H, d, J=2.6 Hz), 6.79 (1H,dd, J=8.5, 2.6 Hz), 7.38 (1H, d, J=8.7 Hz), 7.52 (1H, d, J=8.7 Hz), 7.73(1H, dd, J=8.7, 2.3 Hz), 7.88 (1H, d, J=2.3 Hz), 9.50 (1H, s) (Theexchangeable 1H was not observed).

(Step 7)

To a solution of(R)—N-(4-(tert-butyl)-3-cyanophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(100 mg, 0.28 mmol), DIEA (0.094 mL, 0.55 mmol) and2-(3-hydroxy-1,2-oxazol-5-yl)acetic acid (47.2 mg, 0.33 mmol) in DMF(2.0 mL) was added HATU (126 mg, 0.33 mmol), and the mixture was stirredat room temperature for 2 hr. To the reaction mixture was added water,and the mixture was extracted with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 0→50% ethylacetate/hexane), and crystallized from ethyl acetate/hexane to give thetitle compound (38.7 mg, 0.079 mmol, 28.8%) as white crystals.

MS(API): Calculated 488.5. Found 487.0 (M−H).

¹H NMR (300 MHz, DMSO-d): δ 1.42 (9H, s), 2.72-2.90 (1H, m), 3.05-3.20(1H, m), 3.52-3.65 (1H, m), 3.73 (3H, s), 3.93-4.14 (3H, m), 5.61-5.75(1H, m), 5.82-5.96 (1H, m), 6.79-6.89 (2H, m), 7.42-7.55 (2H, m),7.65-7.75 (1H, m), 8.03 (1H, d, J=2.6 Hz), 10.63-10.76 (1H, m), 11.13(1H, s).

Example 66(1R)-6-ethoxy-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

6-Ethoxy-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(213.5 mg) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give(1R)-6-ethoxy-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(108.5 mg, >99.9% ee) as a white solid.

MS(API): Calculated 507.6. Found 508.2 (M+H).

purification condition by chiral column chromatography

column: CHIRALPAK IA (QK001) 50 mmID×500 mmL

solvent: hexane/EtOH/acetic acid=500/500/1

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

[α]_(D) ²⁵ +7.2 (c 0.2500, MeOH)

Example 67(1R)—N-(4-tert-butyl-3-fluorophenyl)-6-ethoxy-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

N-(4-tert-Butyl-3-fluorophenyl)-6-ethoxy-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(434.5 mg) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give(1R)—N-(4-tert-butyl-3-fluorophenyl)-6-ethoxy-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(194.8 mg, >99.9% ee) as a white solid.

MS(API): Calculated 495.5. Found 496.1 (M+H).

purification condition by chiral column chromatography

column: CHIRALPAK IA (QK001) 50 mmID×500 mmL

solvent: hexane/EtOH/acetic acid=500/500/1

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

[α]_(D) ²⁵ +1.6 (c 0.2500, MeOH)

Example 68(1R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

To a solution of(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(500 mg, 1.36 mmol), DIEA (0.464 mL, 2.71 mmol) and3-hydroxy-1,2-oxazole-5-carboxylic acid (193 mg, 1.49 mmol) in DMF (10mL) was added COMU (697 mg, 1.63 mmol) at 0° C., and the mixture wasstirred at room temperature. To the reaction mixture was added water,and the mixture was extracted with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent; 50% ethyl acetate/hexane),and then silica gel column chromatography (Diol, solvent; 50% ethylacetate/hexane) to give the title compound (423.0 mg, 0.882 mmol, 65.0%)as a white solid.

MS(API): Calculated 479.5. Found 480.1 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ 1.28 (6H, d, J=1.5 Hz), 1.87 (2H, t, J=7.4Hz), 2.86 (3H, t, J=7.2 Hz), 3.06-3.25 (1H, m), 3.67-3.80 (4H, m),4.10-4.22 (1H, m), 5.54-5.72 (1H, m), 6.35-6.61 (1H, m), 6.79-6.90 (2H,m), 7.09-7.27 (2H, m), 7.48-7.57 (1H, m), 10.22-10.61 (1H, m), 11.78(1H, brs).

[α]_(D) ²⁵ −10.1 (c 0.2500, MeOH)

Example 69(1R)—N-(3-fluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

A solution of conc. sulfuric acid (1 mL, 18.76 mmol) and2-(2-fluoro-4-nitrophenyl)acetic acid (10 g, 50.22 mmol) in MeOH (200mL) was heated under reflux for 4 hr. To the reaction mixture was addedaqueous sodium hydrogen carbonate solution until the mixture becameneutral, and the mixture was concentrated under reduced pressure. To theresidue were added ethyl acetate and water, and the organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure to give methyl2-(2-fluoro-4-nitrophenyl)acetate (10.70 g, 50.2 mmol, 100%) as a paleyellow solid.

¹H NMR (300 MHz, DMSO-d₆): δ 3.65 (3H, s), 3.93 (2H, d, J=1.1 Hz),7.59-7.78 (1H, m), 8.02-8.21 (2H, m).

(Step 2)

To a solution of methyl 2-(2-fluoro-4-nitrophenyl)acetate (10.7 g, 50.20mmol) and iodomethane (12.55 mL, 200.79 mmol) in DMF (100 mL) was addedsodium hydride (60% oil, 5.02 g, 125.49 mmol) at 0° C., and the mixturewas stirred at 0° C. for 4 hr. To the reaction mixture was added aqueousammonium chloride solution, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 5→20% ethyl acetate/hexane) to givemethyl 2-(2-fluoro-4-nitrophenyl)-2-methylpropanoate (12.10 g, 50.2mmol, 100%) as a yellow solid.

¹H NMR (300 MHz, DMSO-d₆): δ 1.54 (6H, s), 3.61 (3H, s), 7.65-7.82 (1H,m), 8.04-8.15 (2H, m).

(Step 3)

1.5M DIBAL-H/toluene solution (83 mL, 124.37 mmol) was added to asolution of methyl 2-(2-fluoro-4-nitrophenyl)-2-methylpropanoate (10 g,41.46 mmol) in THF (100 mL) at 0° C., and the mixture was stirred atroom temperature for 4 hr. To the reaction mixture was slowly addedsaturated potassium sodium tartrate aqueous solution at 0° C., and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 10→80% ethylacetate/hexane) to give 2-(2-fluoro-4-nitrophenyl)-2-methylpropan-1-ol(8.31 g, 39.0 mmol, 94%) as a brown oil.

¹H NMR (300 MHz, DMSO-dr): δ 1.31 (6H, d, J=1.1 Hz), 3.52-3.66 (2H, m),4.87 (1H, t, J=5.5 Hz), 7.51-7.72 (1H, m), 7.93-8.09 (2H, m).

(Step 4)

Sodium hydride (60% oil, 0.703 g, 17.59 mmol) was slowly added to asolution of iodomethane (1.466 mL, 23.45 mmol) and2-(2-fluoro-4-nitrophenyl)-2-methylpropan-1-ol (2.5 g, 11.73 mmol) inTHF (10 mL) at −10° C., and the mixture was stirred at room temperaturefor 2 hr. To the reaction mixture was added aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent gradient; 0→20% ethyl acetate/hexane) to give2-fluoro-1-(1-methoxy-2-methylpropan-2-yl)-4-nitrobenzene (2.280 g,10.03 mmol, 86%) as a pale yellow oil.

¹H NMR (300 MHz, DMSO-d₆): δ 1.34 (6H, d, J=1.1 Hz), 3.22 (3H, s), 3.53(2H, d, J=1.1 Hz), 7.61 (1H, t, J=8.5 Hz), 7.96-8.05 (2H, m).

(Step 5)

A solution of 2-fluoro-1-(1-methoxy-2-methylpropan-2-yl)-4-nitrobenzene(2.6 g, 11.44 mmol) and 10% palladium-carbon (260 mg, 0.12 mmol, 50%wet) in MeOH (100 mL) was stirred overnight under hydrogen atmosphere (1atm) at room temperature. The catalyst was removed by filtration, andthe filtrate was concentrated under reduced pressure to give3-fluoro-4-(1-methoxy-2-methylpropan-2-yl)aniline (2170 mg, 11.00 mmol,96%) as a pale yellow solid.

¹H NMR (300 MHz, DMSO-d₆): δ 1.21 (6H, s), 3.20 (3H, s), 3.36 (2H, d,J=0.8 Hz), 5.16 (2H, s), 6.17-6.35 (2H, m), 6.89 (1H, dd, J=9.6, 8.5Hz).

(Step 6)

T3P (50% ethyl acetate solution) (4.52 mL, 7.60 mmol) was added to asolution of2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (1.730 g, 3.56 mmol, 70.1%),3-fluoro-4-(1-methoxy-2-methylpropan-2-yl)aniline (1 g, 5.07 mmol), DIEA(4.43 mL, 25.35 mmol) and DMAP (0.681 g, 5.58 mmol) in ethyl acetate(100 mL) at room temperature, and the mixture was stirred at 70° C. for15 hr. To the reaction mixture was added water, and the mixture wasextracted twice with ethyl acetate. The organic layer was washed withaqueous sodium hydrogen carbonate solution and brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 10→70% ethyl acetate/hexane) to givetert-butyl1-((3-fluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.730 g, 3.56 mmol, 70.1%) as white crystals.

¹H NMR (300 MHz, DMSO-d): δ 1.26 (6H, s), 1.31-1.49 (9H, m), 2.74 (1H,dt, J=15.5, 4.7 Hz), 2.95-3.11 (1H, m), 3.20 (3H, s), 3.27-3.37 (1H, m),3.43 (2H, s), 3.72 (3H, s), 3.85-3.98 (1H, m), 5.23-5.53 (1H, m),6.72-6.93 (2H, m), 7.12-7.30 (2H, m), 7.35-7.58 (2H, m), 10.30-10.60(1H, m).

(Step 7)

tert-Butyl1-((3-fluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.44 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((3-fluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.20 g, >99.9% ee) as a white solid.

purification condition by chiral column chromatography

column: CHIRALCEL OD (NF001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 8)

To tert-Butyl(R)-1-((3-fluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(730 mg, 1.50 mmol) was added 4M hydrogen chloride/ethyl acetate (5 mL,20.00 mmol), and the mixture was stirred at room temperature for 2 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was crystallized from ethyl acetate/hexane to give(R)—N-(3-fluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (577 mg, 1.364 mmol, 91%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 1.29 (6H, s), 2.84-3.03 (1H, m), 3.05-3.18(1H, m), 3.22 (3H, s), 3.35-3.49 (3H, m), 3.61-3.72 (1H, m), 3.74 (3H,s), 5.18 (1H, s), 6.82-6.92 (2H, m), 7.25-7.40 (3H, m), 7.46-7.57 (1H,m), 8.88-10.32 (2H, m), 11.32 (1H, s).

(Step 9)

HATU (108 mg, 0.28 mmol) was added to a solution of DIEA (0.124 mL, 0.71mmol), 3-hydroxy-1,2-oxazole-5-carboxylic acid (33.6 mg, 0.26 mmol) and(R)—N-(3-fluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (100 mg, 0.24 mmol) in DMF (2 mL) at room temperature, andthe mixture was stirred overnight at room temperature. To the reactionmixture was added water, and the mixture was extracted three times witha mixed solvent of ethyl acetate/THF. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 50→100% ethyl acetate/hexane)to give the title compound (37.0 mg, 0.074 mmol, 31.5%) as a whitesolid.

MS(API): Calculated 497.5. Found 498.0 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ 1.26 (6H, s), 2.87 (1H, d, J=15.5 Hz), 3.14(1H, d, J=8.7 Hz), 3.19 (3H, s), 3.43 (2H, s), 3.74 (4H, s), 4.02-4.24(1H, m), 5.69 (1H, s), 6.55 (1H, s), 6.78-6.91 (2H, m), 7.15-7.28 (2H,m, J=5.3 Hz), 7.39-7.56 (2H, m), 10.66 (1H, s), 11.86 (1H, brs).

Example 70(1R)—N-(3-fluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

HATU (108 mg, 0.28 mmol) was added to a solution of DIEA (0.124 mL, 0.71mmol), 2-(3-hydroxy-1,2-oxazol-5-yl)acetic acid (37.2 mg, 0.26 mmol) and(R)—N-(3-fluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (100 mg, 0.24 mmol) in DMF (2 mL) at room temperature, andthe mixture was stirred overnight. To the reaction mixture was addedwater, and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 50→100%ethyl acetate/hexane) to give the title compound (12.00 mg, 0.023 mmol,9.92-) as a white solid.

MS(API): Calculated 511.5. Found 512.1 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ 1.26 (6H, s), 2.85 (1H, brs), 3.13 (1H, s),3.19 (3H, s), 3.42 (2H, s), 3.63 (1H, s), 3.73 (3H, s), 3.86-4.14 (3H,m), 5.67 (1H, s), 5.90 (1H, s), 6.74-6.88 (2H, m), 7.11-7.27 (2H, m),7.37-7.54 (2H, m), 10.54 (1H, s), 11.12 (1H, brs).

Example 71N-(4-(2,2-dimethylpropyl)-3-fluorophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

The title compound was synthesized using 3-fluoro-4-neo-pentylaniline,by the reaction and purification in the same manner as in Example 65.

Example 72(1R)—N-(3-cyano-4-(trimethylsilyl)phenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

A solution of 2-chloro-5-nitrobenzonitrile (19.5 g, 106.81 mmol), HMDS(43.7 mL, 213.62 mmol), Pd₂(dba)₃ (2.93 g, 3.20 mmol),2′-(di-tert-butylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (3.28g, 9.61 mmol), water (3.85 g, 213.62 mmol) and lithium acetate (35.2 g,534.06 mmol) in DMF (400 mL) was stirred under argon gas atmosphere at100° C. for 5 hr. To the reaction mixture were added water and ethylacetate, and the organic layer was separated. The organic layer wasdried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→5% ethyl acetate/hexane) to give5-nitro-2-(trimethylsilyl)benzonitrile (13.2 g, 59.9 mmol, 56.1%) as awhite solid.

(Step 2)

A solution of 5-nitro-2-(trimethylsilyl)benzonitrile and 10%palladium-carbon (1.32 g, 0.62 mmol, 50% wet) in MeOH (260 mL) wasstirred under hydrogen atmosphere (1 atm) at room temperature for 5 hr.The catalyst was removed by filtration, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 10→20% ethylacetate/hexane) to give 5-amino-2-(trimethylsilyl)benzonitrile (9.56 g,50.2 mmol, 84%) as a white solid.

(Step 3)

To a solution of2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (1.776 g, 5.78 mmol), DMAP (0.706 g, 5.78 mmol) and DIEA (4.59 mL,26.27 mmol) in ethyl acetate (30 mL) was added T3P (6.18 mL, 10.51 mmol)at room temperature, and the mixture was stirred at 80° C. for 2 hr. Tothe reaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→20% ethyl acetate/hexane), andcrystallized from diethyl ether/hexane to give tert-butyl1-((3-cyano-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(758 mg, 1.580 mmol, 30.1%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 0.38 (9H, s), 1.53 (9H, s), 2.81-2.99 (2H,m), 3.50-3.75 (2H, m), 3.80 (3H, s), 5.57-5.69 (1H, m), 6.74 (1H, d,J=2.3 Hz), 6.81 (1H, dd, J=8.5, 2.3 Hz), 7.19 (1H, brs), 7.48 (1H, d,J=7.9 Hz), 7.62 (1H, dd, J=8.1, 2.1 Hz), 7.90 (1H, d, J=2.1 Hz),8.82-9.44 (1H, m).

(Step 4)

tert-Butyl1-((3-cyano-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(758 mg) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((3-cyano-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(310 mg, >99.5% ee) as a white solid.

purification condition by chiral column chromatography

column: CHIRALCEL OD (NL001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 5)

Cooled TFA (3.0 mL) was added to tert-butyl(R)-1-((3-cyano-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(310 mg, 0.65 mmol) at room temperature, and the mixture was stirred atroom temperature for 2 min. The reaction mixture was added to ice andaqueous sodium hydrogen carbonate solution, and aqueous sodium hydrogencarbonate solution was added thereto until the pH of the mixture became8. Then, the mixture was extracted with ethyl acetate. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure to give(R)—N-(3-cyano-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(228.6 mg, 0.602 mmol, 93%) as a white solid.

(Step 6)

To a solution of(R)—N-(3-cyano-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(100 mg, 0.26 mmol), DIEA (0.090 mL, 0.53 mmol) and2-(3-hydroxy-1,2-oxazol-5-yl)acetic acid (45.2 mg, 0.32 mmol) in DMF(2.0 mL) was added HATU (120 mg, 0.32 mmol) at room temperature, and themixture was stirred at room temperature for 2 hr. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→50% ethyl acetate/hexane), andcrystallized from ethyl acetate/hexane to give the title compound (46.6mg, 0.092 mmol, 35.0%) as white crystals.

MS(API): Calculated 504.6. Found 505.1 (M+H).

¹H NMR (300 MHz, DMSO-d): δ 0.34 (9H, s), 2.76-2.92 (1H, m), 3.05-3.20(1H, m), 3.50-3.65 (1H, m), 3.73 (3H, s), 3.90-4.18 (3H, m), 5.74 (1H,s), 5.79-5.94 (1H, m), 6.74-6.92 (2H, m), 7.50 (1H, d, J=8.7 Hz), 7.60(1H, d, J=8.3 Hz), 7.76 (1H, dd, J=8.3, 2.3 Hz), 8.06 (1H, d, J=1.9 Hz),10.77 (1H, s), 11.14 (1H, brs).

Example 73(1R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

To a solution of 3-fluoro-4-(trimethylsilyl)aniline (1.2 g, 6.55 mmol),2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (2.213 g, 7.20 mmol), DMAP (0.880 g, 7.20 mmol) and DIEA (5.72 mL,32.73 mmol) in ethyl acetate (30 mL) was added T3P (11.55 mL, 19.64mmol) at room temperature, and the mixture was stirred at 80° C. for 2hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→20% ethyl acetate/hexane), andcrystallized from diethyl ether/hexane to give tert-butyl1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.75 g, 3.70 mmol, 56.6%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 0.27 (9H, s), 1.52 (9H, s), 2.75-2.97 (2H,m), 3.46-3.76 (2H, m), 3.80 (3H, s), 5.60 (1H, brs), 6.72 (1H, d, J=2.3Hz), 6.81 (1H, dd, J=8.3, 2.3 Hz), 7.10 (1H, d, J=7.6 Hz), 7.26-7.33(2H, m), 7.39 (1H, dd, J=10.6, 1.5 Hz), 8.95 (1H, brs).

(Step 2)

Cooled TFA (3.0 mL) was added to tert-butyl1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(794 mg, 1.68 mmol) at room temperature, and the mixture was stirred atroom temperature for 2 min. The pH of the reaction mixture was adjustedto 8 with ice and aqueous sodium hydrogen carbonate solution. Then, themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure to giveN-(3-fluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(642.6 mg, 1.725 mmol, 103%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.27 (9H, d, J=0.8 Hz), 2.68-2.98 (2H, m),3.08-3.26 (2H, m), 3.78 (3H, s), 4.74 (1H, s), 6.64 (1H, d, J=2.6 Hz),6.78 (1H, dd, J=8.5, 2.6 Hz), 7.11-7.20 (1H, m), 7.23-7.30 (1H, m),7.37-7.52 (2H, m), 9.49 (1H, brs) (The exchangeable 1H was notobserved).

(Step 3)

To a solution ofN-(3-fluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(100 mg, 0.27 mmol), DIEA (0.092 mL, 0.54 mmol) and2-(3-hydroxy-1,2-oxazol-5-yl)acetic acid (46.1 mg, 0.32 mmol) in DMF(2.0 mL) was added HATU (122 mg, 0.32 mmol) at 0° C., and the mixturewas stirred at room temperature for 2 hr. To the reaction mixture wasadded water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 0→50% ethyl acetate/hexane), and crystallized from ethylacetate/hexane to giveN-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(2-(3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(35.3 mg, 0.071 mmol, 26.4%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 0.21-0.28 (9H, m), 2.72-2.90 (1H, m),3.03-3.21 (1H, m), 3.49-3.66 (1H, m), 3.69-3.76 (3H, m), 3.87-4.14 (3H,m), 5.64-5.73 (1H, m), 5.82-5.95 (1H, m), 6.78-6.87 (2H, m), 7.25-7.38(2H, m), 7.41-7.53 (2H, m), 10.64 (1H, s), 11.12 (1H, brs).

(Step 4)

N-(3-Fluoro-4-(trimethylsilyl)phenyl)-2-(2-(3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(380 mg) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give the titlecompound (160 mg, >98.8% ee) as a white solid.

MS(API): Calculated 497.6. Found 498.1 (M+H).

purification condition by chiral column chromatography

column: CHIRALPAK IC (1F001) 50 mmID×500 mmL

solvent: hexane/EtOH/acetic acid=500/500/1

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

[α]_(D) ²⁵ +8.0 (c 0.2550, MeOH)

Example 74(1R)—N-(4-fluoro-3,3-dimethyl-2,3-dihydro-1-benzofuran-6-yl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

The title compound was synthesized using4-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-6-amine, by the reaction andpurification in the same manner as in Example 65.

Example 75(1R)—N-(4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3-fluorophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (Step1)

Sodium hydride (60% oil, 0.563 g, 14.07 mmol) was slowly added to asolution of 2,2-difluoroethyl trifluoromethanesulfonate (3.01 g, 14.07mmol) and 2-(2-fluoro-4-nitrophenyl)-2-methylpropan-1-ol (2.5 g, 11.73mmol) in THF (100 mL) at −10° C., and the mixture was stirred at roomtemperature for 2 hr. To the reaction mixture was added aqueous sodiumhydrogen carbonate solution, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→20% ethyl acetate/hexane) to give1-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-2-fluoro-4-nitrobenzene(2.88 g, 10.39 mmol, 89%) as a pale yellow oil.

¹H NMR (300 MHz, DMSO-d₆): δ 1.36 (6H, d, J=0.8 Hz), 3.67 (2H, td,J=15.3, 3.8 Hz), 3.74 (2H, s), 5.83-6.33 (1H, m), 7.57-7.69 (1H, m),7.98-8.09 (2H, m).

(Step 2)

A solution of1-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-2-fluoro-4-nitrobenzene(2.88 g, 10.39 mmol) and 10% palladium-carbon (300 mg, 0.014 mmol, 50%wet) in MeOH (100 mL) was stirred overnight under hydrogen atmosphere (1atm) at room temperature. The catalyst was removed by filtration, andthe filtrate was concentrated under reduced pressure to give4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3-fluoroaniline (2440 mg,9.87 mmol, 95%) as a brown oil.

¹H NMR (300 MHz, DMSO-d₆): δ 1.23 (6H, s), 3.56 (2H, s), 3.57-3.70 (2H,m), 5.19 (2H, s), 5.86-6.27 (1H, m), 6.21-6.34 (2H, m), 6.6.34 (1H, m),6.82-7.01 (1H, m).

(Step 3)

T3P (3.61 mL, 6.07 mmol) was added to a solution of4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3-fluoroaniline (1 g,4.04 mmol),2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (1.243 g, 4.04 mmol), DIEA (3.53 mL, 20.22 mmol) and DMAP (0.544 g,4.45 mmol) in ethyl acetate (100 mL) at room temperature, and themixture was stirred at 70° C. for 15 hr. To the reaction mixture wasadded water, and the mixture was extracted twice with ethyl acetate. Theorganic layer was washed with aqueous sodium hydrogen carbonate solutionand brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 10→70% ethylacetate/hexane) to give tert-butyl1-((4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3-fluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.508 g, 0.947 mmol, 23.41%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 1.22-1.46 (15H, m), 2.74 (1H, d, J=15.5Hz), 3.05 (1H, brs), 3.33-3.50 (1H, m), 3.54-3.69 (4H, m), 3.72 (3H, s),3.86-4.03 (1H, m), 5.24-5.48 (1H, m), 5.82-6.34 (1H, m), 6.71-6.89 (2H,m), 7.13-7.31 (2H, m), 7.37-7.54 (2H, m), 10.30-10.61 (1H, m).

(Step 4)

tert-Butyl1-((4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3-fluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.508 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3-fluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(230 mg, >99.8% ee) as a white solid.

purification condition by chiral column chromatography

column: CHIRALCEL OD (NL001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 5)

To tert-butyl(R)-1-((4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3-fluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(230 mg, 0.43 mmol) was added 4M hydrogen chloride/ethyl acetate (5 mL,20.00 mmol) at room temperature, and the mixture was stirred at roomtemperature for 2 hr. The reaction mixture was concentrated underreduced pressure, and the residue was crystallized from ethylacetate/hexane to give(R)—N-(4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3-fluorophenyl)-6-methoxy-,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (207 mg, 0.438mmol, 102%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 1.31 (6H, s), 2.87-3.03 (1H, m), 3.06-3.15(1H, m), 3.40 (1H, d, J=12.8 Hz), 3.59-3.73 (5H, m), 3.74 (3H, s), 5.20(1H, s), 5.85-6.31 (1H, m), 6.81-6.95 (2H, m), 7.27-7.40 (3H, m),7.46-7.59 (1H, m), 9.36 (1H, brs), 9.95 (1H, brs), 11.36 (1H, s).

(Step 6)

HATU (105 mg, 0.27 mmol) was added to a solution of DIEA (0.111 mL, 0.63mmol), 3-hydroxy-1,2-oxazole-5-carboxylic acid (32.8 mg, 0.25 mmol) and(R)—N-(4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3-fluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (100 mg, 0.21 mmol) in DMF (2 mL) at room temperature, andthe mixture was stirred overnight. To the reaction mixture was addedwater, and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 50→100%ethyl acetate/hexane) to give the title compound (28.0 mg, 0.051 mmol,24.19%) as a white solid.

MS(API): Calculated 547.5. Found 546.0 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ 1.22-1.33 (6H, m), 2.87 (1H, d, J=17.0 Hz),3.08-3.22 (1H, m), 3.54-3.69 (4H, m), 3.74 (4H, s), 4.08-4.23 (1H, m),5.69 (1H, s), 5.83-6.28 (1H, m), 6.55 (1H, s), 6.79-6.90 (2H, m),7.17-7.30 (2H, m), 7.42-7.58 (2H, m), 10.67 (1H, s), 11.67-12.08 (1H,m).

Example 77(5R)—N-(4-tert-butyl-3-fluorophenyl)-6-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-2-methoxy-5,6,7,8-tetrahydro-,6-naphthyridine-5-carboxamide (Step 1)

tert-Butyl5-((4-(tert-butyl)-3-fluorophenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(3.47 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-5-((4-(tert-butyl)-3-fluorophenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.47 g, >99.9% ee) as a white solid.

MS(API): Calculated 468.5. Found 469.1 (M+H).

purification condition by chiral column chromatography

column: CHIRALPAK IA (QK001) 50 mmID×500 mmL

solvent: hexane/EtOH=600/400

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 2)

Cooled TFA (20 mL) was added to tert-butyl(R)-5-((4-(tert-butyl)-3-fluorophenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.47 g, 3.21 mmol) at room temperature, and the mixture was stirred atroom temperature for 15 min. The reaction mixture was added to ice andaqueous sodium hydrogen carbonate solution, and potassium carbonate wasadded thereto until the pH of the mixture became 8. Then, the mixturewas extracted three times with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure to give(R)—N-(4-(tert-butyl)-3-fluorophenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(1.05 g, 2.94 mmol, 91%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.34 (9H, d, J=0.8 Hz), 1.75 (1H, brs),2.74-2.85 (1H, m), 2.87-2.99 (1H, m), 3.13-3.29 (2H, m), 3.90 (3H, s),4.58 (1H, s), 6.60 (1H, d, J=8.7 Hz), 7.11 (1H, dd), 7.20 (1H, t), 7.43(1H, dd, J=14.4, 2.3 Hz), 7.83 (1H, d, J=8.7 Hz), 9.44 (1H, s).

(Step 3)

HATU (249 mg, 0.65 mmol) was added to a solution of(R)—N-(4-(tert-butyl)-3-fluorophenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(180 mg, 0.50 mmol), 3-hydroxy-1,2-oxazole-5-carboxylic acid (78 mg,0.60 mmol) and DIEA (175 μL, 1.00 mmol) in DMF (2.5 mL) at roomtemperature, and the mixture was stirred for 15 hr. To the reactionmixture was added water, and the mixture was extracted three times withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 30→100% ethyl acetate/hexane) to givethe title compound (110.6 mg, 0.236 mmol, 46.9%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.34 (9H, s), 2.83 (1H, s), 3.00-3.10 (1H,m), 3.15-3.29 (1H, m), 3.78-3.89 (1H, m), 3.93 (3H, s), 4.32-4.42 (1H,m), 5.97 (1H, s), 6.58 (1H, s), 6.68 (1H, d, J=8.7 Hz), 7.11 (1H, dd),7.21 (1H, t), 7.36-7.44 (2H, m), 8.96 (1H, s).

Example 78(5R)—N-(4-tert-butyl-3-fluorophenyl)-6-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide

HATU (249 mg, 0.65 mmol) was added to a solution of(R)—N-(4-(tert-butyl)-3-fluorophenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(180 mg, 0.50 mmol), 2-(3-hydroxy-1,2-oxazol-5-yl)acetic acid (86 mg,0.60 mmol) and DIEA (175 μL, 1.00 mmol) in DMF (2.5 mL) at roomtemperature, and the mixture was stirred for 15 hr. To the reactionmixture was added water, and the mixture was extracted three times withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 20→90% ethyl acetate/hexane), andcrystallized from diisopropyl ether/hexane to give the title compound(95.0 mg, 0.197 mmol, 39.1%) as white crystals.

MS(API): Calculated 482.5. Found 483.1 (M+H).

¹H NMR (300 MHz, CDCl₃): δ 1.30 (9H, s), 2.88-3.01 (1H, m), 3.08-3.18(1H, m), 3.89 (3H, s), 3.91-4.00 (4H, m), 5.96 (1H, s), 5.98 (1H, s),6.64 (1H, d, J=8.3 Hz), 6.94 (1H, dd, J=8.5, 2.1 Hz), 7.10 (1H, t),7.24-7.31 (2H, m), 7.44 (1H, d, J=8.7 Hz), 9.07 (1H, s).

Example 79(5R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-2-methoxy-5,6,7,8-tetrahydro-,6-naphthyridine-5-carboxamide (Step 1)

T3P (8.45 mL, 14.21 mmol) was added to a solution of6-(tert-butoxycarbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylicacid (2.92 g, 9.47 mmol), 3-fluoro-4-(trimethylsilyl)aniline (1.736 g,9.47 mmol), DIEA (8.25 mL, 47.35 mmol) and DMAP (1.273 g, 10.42 mmol) inethyl acetate (70 mL) at room temperature, and the mixture was stirredat 65° C. for 15 hr. To the reaction mixture was added water, and themixture was extracted three times with ethyl acetate. The organic layerwas washed with 10% aqueous citric acid solution, aqueous sodiumhydrogen carbonate solution and brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The precipitatewas washed with cooled hexane to give tert-butyl5-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(3.66 g, 7.73 mmol, 82%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 0.28 (9H, s), 1.53 (9H, s), 2.84-3.03 (2H,m), 3.46 (1H, brs), 3.92 (3H, s), 4.01-4.12 (1H, m), 5.59 (1H, brs),6.64 (1H, d, J=8.3 Hz), 7.11 (1H, dd, J=8.1, 1.3 Hz), 7.29 (1H, dd,J=7.9, 6.4 Hz), 7.39 (1H, dd, J=10.6, 1.9 Hz), 7.47 (1H, brs), 8.94 (1H,brs).

(Step 2)

tert-Butyl5-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(3.66 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-5-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.76 g, >99.9% ee) as a white solid.

purification condition by chiral column chromatography

column: CHIRALPAK IA (QK001) 50 mmID×500 mmL

solvent: hexane/EtOH=600/400

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

Cooled TFA (24 mL) was added to tert-butyl(R)-5-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.76 g, 3.72 mmol) at room temperature, and the mixture was stirred atroom temperature for 2 min. The reaction mixture was added to ice andaqueous sodium hydrogen carbonate solution, and potassium carbonate wasadded thereto until the pH of the mixture became 8. Then, the mixturewas extracted three times with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure to give(R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(1.37 g, 3.67 mmol, 99%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.28 (9H, s), 2.00 (1H, brs), 2.75-2.86 (1H,m), 2.87-2.99 (1H, m), 3.14-3.30 (2H, m), 3.90 (3H, s), 4.60 (1H, s),6.60 (1H, d, J=8.7 Hz), 7.17 (1H, dd), 7.25-7.32 (1H, m), 7.44 (1H, dd,J=10.6, 1.5 Hz), 7.83 (1H, d, J=8.7 Hz), 9.55 (1H, brs).

(Step 4)

HATU (249 mg, 0.65 mmol) was added to a solution of(R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(188 mg, 0.50 mmol), 3-hydroxy-1,2-oxazole-5-carboxylic acid (78 mg,0.60 mmol) and DIEA (175 μL, 1.00 mmol) in DMF (2.5 mL) at roomtemperature, and the mixture was stirred for 15 hr. To the reactionmixture was added water, and the mixture was extracted three times withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 20→90% ethyl acetate/hexane) togive the title compound (94.5 mg, 0.195 mmol, 38.7%) as a white solid.

MS(API): Calculated 484.6. Found 485.2 (M+H).

¹H NMR (300 MHz, CDCl₃): δ 0.28 (9H, s), 2.83 (1H, s), 3.01-3.10 (1H,m), 3.16-3.29 (1H, m), 3.78-3.89 (1H, m), 3.93 (3H, s), 4.32-4.42 (1H,m), 5.97 (1H, s), 6.58 (1H, s), 6.68 (1H, d, J=8.7 Hz), 7.16 (1H, dd,J=7.9, 1.5 Hz), 7.30 (1H, dd), 7.36-7.44 (2H, m), 9.07 (1H, s).

[α]_(D) ²⁵ +91.9 (c 0.2500, MeOH)

Example 80(5R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-2-methoxy-5,6,7,8-tetrahydro-,6-naphthyridine-5-carboxamide

HATU (249 mg, 0.65 mmol) was added to a solution of(R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(188 mg, 0.50 mmol), 2-(3-hydroxy-1,2-oxazol-5-yl)acetic acid (86 mg,0.60 mmol) and DIEA (175 μL, 1.00 mmol) in DMF (2.5 mL) at roomtemperature, and the mixture was stirred for 15 hr. To the reactionmixture was added water, and the mixture was extracted three times withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 20→90% ethyl acetate/hexane),and crystallized from diisopropyl ether/hexane to give the titlecompound (97.8 mg, 0.196 mmol, 39.0%) as white crystals.

MS(API): Calculated 498.6. Found 499.1 (M+H).

¹H NMR (300 MHz, CDCl₃): δ 0.25 (9H, s), 2.88-3.02 (1H, m), 3.08-3.18(1H, m), 3.89 (3H, s), 3.91-3.99 (4H, m), 5.96 (1H, s), 5.99 (1H, s),6.65 (1H, d, J=8.7 Hz), 7.00 (1H, dd, J=7.9, 1.9 Hz), 7.20 (1H, dd,J=7.9, 6.4 Hz), 7.25-7.30 (2H, m), 7.44 (1H, d, J=8.3 Hz), 9.12 (1H, s).

[α]_(D) ²⁵ +105.8 (c 0.2500, MeOH)

Example 81(1R)—N-(4-fluoro-3,3-dimethyl-2,3-dihydro-1-benzofuran-6-yl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

The title compound was synthesized using4-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-6-amine, by the reaction,purification and resolution in the same manner as in Example 3.

Example 825-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid (Step 1)

To a solution of 3,5-difluoro-4-(trimethylsilyl)aniline (700 mg, 3.48mmol),2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (1176 mg, 3.83 mmol), DMAP (467 mg, 3.83 mmol) and DIEA (3.04 mL,17.39 mmol) in ethyl acetate (6.0 mL) was added T3P (6.14 mL, 10.43mmol) at room temperature, and the mixture was stirred at 80° C. for 2hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The precipitate was washed with diethyl ether/hexaneto give tert-butyl1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(994.1 mg, 2.026 mmol, 58.3%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 0.32 (9H, s), 1.52 (9H, s), 2.76-2.98 (2H,m), 3.51-3.75 (2H, m), 3.80 (3H, s), 5.58 (1H, brs), 6.73 (1H, d, J=2.3Hz), 6.81 (1H, dd, J=8.3, 2.3 Hz), 6.97-7.07 (2H, m), 7.19 (1H, brs),9.11 (1H, brs).

(Step 2)

tert-Butyl1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(900 mg) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(410 mg, >99.6% ee) as a white solid.

purification condition by chiral column chromatography

column: CHIRALPAK AD (NF001) 50 mmID×500 mmL

solvent: hexane/EtOH=850/150

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

Cooled TFA (4.5 mL) was added to tert-butyl(R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(439 mg, 0.89 mmol) at room temperature, and the mixture was stirred atroom temperature for 2 min. The reaction mixture was added to ice andaqueous sodium hydrogen carbonate solution, and potassium carbonate wasadded thereto until the pH of the mixture became 8. Then, the mixturewas extracted three times with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The precipitate was washed withIPE/hexane to give(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(246 mg, 0.630 mmol, 70.4%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 0.27 (9H, d, J=1.1 Hz), 2.23 (1H, brs),2.69-2.80 (1H, m), 2.84-2.94 (1H, m), 3.14 (2H, t, J=5.9 Hz), 3.78 (3H,s), 4.63 (1H, s), 6.64 (1H, d, J=2.6 Hz), 6.78 (1H, dd, J=8.7, 2.6 Hz),7.17 (1H, dd), 7.24-7.30 (1H, m), 7.45 (1H, dd, J=10.6, 1.9 Hz), 7.53(1H, d, J=8.7 Hz), 9.45 (1H, s).

(Step 4)

A solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(80 mg, 0.20 mmol), dihydro-2H-pyran-2,6(3H)-dione (28.1 mg, 0.25 mmol)and TEA (0.034 mL, 0.25 mmol) in THF (2.0 mL) was stirred overnight atroom temperature. The reaction mixture was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 10→50% ethyl acetate/hexane) togive the title compound (42.2 mg, 0.084 mmol, 40.8%) as a white solid.

MS(API): Calculated 504.6. Found 503.0 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ 0.29 (9H, s), 1.63-1.82 (2H, m), 2.18-2.32(3H, m), 2.36-2.49 (1H, m), 2.52-2.61 (1H, m), 2.72-2.88 (1H, m),3.05-3.19 (1H, m), 3.43-3.56 (1H, m), 3.73 (3H, s), 5.56-5.67 (1H, m),6.77-6.86 (2H, m), 7.15-7.25 (2H, m), 7.46 (1H, d, J=9.1 Hz), 10.76 (1H,s), 12.01 (1H, brs).

[α]_(D) ²⁵ −6.6 (c 0.2500, MeOH)

Example 834-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutanoicacid

The title compound was synthesized using dihydrofuran-2,5-dione, by thereaction and purification in the same manner as in Example 82.

Example 84(1R)—N-(4-tert-butyl-3,5-difluorophenyl)-2-(cyanoacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

HATU (222 mg, 0.58 mmol) was added to a solution of DIEA (0.255 mL, 1.46mmol), 2-cyanoacetic acid (45.5 mg, 0.54 mmol) and(R)—N-(4-(tert-butyl)-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (200 mg, 0.49 mmol) in DMF (5 mL), and the mixture wasstirred overnight at room temperature. To the reaction mixture was addedwater, and the mixture was extracted with ethyl acetate.

The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent gradient; 30→100% ethyl acetate/hexane) to give the titlecompound (154 mg, 0.349 mmol, 71.7%) as a white solid.

MS(API): Calculated 441.5. Found 440.0 (M−H).

¹H NMR (300 MHz, DMSO-d): δ 1.38 (9H, t, J=1.9 Hz), 2.79-2.94 (1H, m),3.01-3.21 (1H, m), 3.40-3.52 (1H, m), 3.73 (3H, s), 3.86-4.02 (1H, m),4.08-4.39 (2H, m), 5.62 (1H, s), 6.84 (2H, dd, J=4.3, 1.7 Hz), 7.06-7.30(2H, m), 7.41-7.52 (1H, m), 10.69 (1H, s).

Example 85(1R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

To a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(70 mg, 0.18 mmol), DIEA (0.061 mL, 0.36 mmol) and2-(3-hydroxy-1,2-oxazol-5-yl)acetic acid (30.8 mg, 0.22 mmol) in DMF(2.0 mL) was added HATU (82 mg, 0.22 mmol) at room temperature, and themixture was stirred overnight at room temperature. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→50% ethyl acetate/hexane), andcrystallized from ethyl acetate/hexane to give the title compound (39.0mg, 0.076 mmol, 42.2%) as white crystals.

MS(API): Calculated 515.6. Found 516.1 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ 0.29 (9H, s), 2.71-2.90 (1H, m), 3.05-3.21(1H, m), 3.49-3.64 (1H, m), 3.73 (3H, s), 3.90-4.14 (3H, m), 5.59-5.72(1H, m), 5.82-5.93 (1H, m), 6.79-6.88 (2H, m), 7.13-7.25 (2H, m), 7.47(1H, d, J=9.4 Hz), 10.72-10.83 (1H, m), 11.12 (1H, s).

Example 865-((1R)-1-((4-(ethyl(dimethyl)silyl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid (Step 1)

To a solution of 1,3-difluoro-5-nitrobenzene (3 g, 18.86 mmol) andchloro(ethyl)dimethylsilane (3.47 g, 28.29 mmol) in THF (45 mL) wasadded 1.9M NaHMDS/THF solution (12.90 mL, 24.51 mmol) under argon gasatmosphere at −78° C., and the mixture was stirred at −78° C. for 1 hr.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent; hexane) to give (2,6-difluoro-4-nitrophenyl)(ethyl)dimethylsilane (2.93 g, 11.94 mmol, 63.3%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 0.36-0.42 (6H, m), 0.83-0.92 (2H, m),0.93-1.03 (3H, m), 7.61-7.70 (2H, m).

(Step 2)

A solution of (2,6-difluoro-4-nitrophenyl) (ethyl)dimethylsilane (2.9 g,11.82 mmol) and 10% palladium-carbon (300 mg, 0.14 mmol, 50% wet) inMeOH (50 mL) was stirred under hydrogen atmosphere (1 atm) at roomtemperature for 5 hr. The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (solvent gradient;10→20% MeOH/ethyl acetate) to give4-(ethyldimethylsilyl)-3,5-difluoroaniline (2.32 g, 10.77 mmol, 91%) asa colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 0.24-0.32 (6H, m), 0.70-0.83 (2H, m),0.89-1.00 (3H, m), 3.89 (2H, brs), 6.05-6.14 (2H, m).

(Step 3)

To a solution of 4-(ethyldimethylsilyl)-3,5-difluoroaniline (700 mg,3.25 mmol),2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (1099 mg, 3.58 mmol), DMAP (437 mg, 3.58 mmol) and DIEA (2.84 mL,16.26 mmol) in ethyl acetate (20 mL) was added T3P (5.74 mL, 9.75 mmol)at room temperature, and the mixture was stirred at 80° C. for 2 hr. Tothe reaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→10% ethyl acetate/hexane), andcrystallized from diethyl ether/hexane to give tert-butyl1-((4-(ethyldimethylsilyl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(983.2 mg, 1.948 mmol, 59.9%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 0.26-0.34 (6H, m), 0.72-0.86 (2H, m), 0.92(3H, q, J=7.4 Hz), 1.52 (9H, s), 2.74-2.98 (2H, m), 3.46-3.75 (2H, m),3.80 (3H, s), 5.58 (1H, brs), 6.73 (1H, d, J=2.3 Hz), 6.81 (1H, dd,J=8.7, 2.3 Hz), 6.96-7.07 (2H, m), 7.19 (1H, brs), 9.11 (1H, brs).

(Step 4)

tert-Butyl1-((4-(ethyldimethylsilyl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.0 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((4-(ethyldimethylsilyl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.48 g, >99.8% ee) as a white solid.

purification condition by chiral column chromatography

column: CHIRALPAK AD (NF001) 50 mmID×500 mmL

solvent: hexane/EtOH=850/150

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 5)

Cooled TFA (4.5 mL) was added to tert-butyl(R)-1-((4-(ethyldimethylsilyl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(475 mg, 0.94 mmol) at room temperature, and the mixture was stirred atroom temperature for 2 min. The reaction mixture was added to ice andaqueous sodium hydrogen carbonate solution, and potassium carbonate wasadded thereto until the pH of the mixture became 8. Then, the mixturewas extracted three times with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The precipitate was washed withdiethyl ether/IPE to give(R)—N-(4-(ethyldimethylsilyl)-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(853.8 mg, 2.111 mmol, 224%) as white crystals.

(Step 6)

A solution of(R)—N-(4-(ethyldimethylsilyl)-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(160 mg, 0.40 mmol), dihydro-2H-pyran-2,6(3H)-dione (54.2 mg, 0.47 mmol)and TEA (0.066 mL, 0.47 mmol) in THF (4.0 mL) was stirred overnight atroom temperature. The reaction mixture was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 10→50% ethyl acetate/hexane) togive the title compound (85.7 mg, 0.165 mmol, 41.8%) as white crystals.

MS(API): Calculated 518.6. Found 519.1 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ 0.28 (6H, s), 0.66-0.80 (2H, m), 0.83-0.94(3H, m), 1.64-1.82 (2H, m), 2.17-2.32 (3H, m), 2.35-2.61 (1H, m),2.70-2.88 (1H, m), 3.00-3.20 (1H, m), 3.42-3.57 (1H, m), 3.73 (3H, s),3.95-4.09 (1H, m), 5.56-5.65 (1H, m), 6.77-6.87 (2H, m), 7.14-7.26 (2H,m), 7.46 (1H, d, J=9.4 Hz), 10.76 (1H, s), 12.01 (1H, s).

[α]_(D) ²⁵ −7.6 (c 0.2500, MeOH)

Example 874-((1R)-1-((4-(ethyl(dimethyl)silyl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutanoicacid

The title compound was synthesized using dihydrofuran-2,5-dione, by thereaction and purification in the same manner as in Example 86.

Example 88(1R)—N-(4-(ethyl(dimethyl)silyl)-3,5-difluorophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

To a solution of(R)—N-(4-(ethyldimethylsilyl)-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(80 mg, 0.20 mmol), DIEA (0.068 mL, 0.40 mmol) and2-(3-hydroxy-1,2-oxazol-5-yl)acetic acid (34.0 mg, 0.24 mmol) in DMF(2.0 mL) was added HATU (90 mg, 0.24 mmol) at room temperature, and themixture was stirred overnight. To the reaction mixture was added water,and the mixture was extracted with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 0→50% ethylacetate/hexane), and crystallized from ethyl acetate/hexane to give thetitle compound (24.9 mg, 0.047 mmol, 23.77%) as white crystals.

MS(API): Calculated 529.6. Found 530.1 (M+H).

¹H NMR (300 MHz, DMSO-d): δ 0.28 (6H, s), 0.67-0.79 (2H, m), 0.83-0.93(3H, m), 2.75-2.90 (1H, m), 3.05-3.22 (1H, m), 3.48-3.63 (1H, m), 3.73(3H, s), 3.90-4.15 (3H, m), 5.58-5.73 (1H, m), 5.82-5.95 (1H, m),6.76-6.90 (2H, m), 7.13-7.27 (2H, m), 7.40-7.53 (1H, m), 10.72-10.86(1H, m), 11.11 (1H, brs).

Example 89(1R)—N-(3,5-difluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

The title compound was synthesized using2-(4-amino-2,6-difluorophenyl)-2-methyl-1-(pyrrolidin-1-yl)propan-1-one,by the reaction and purification in the same manner as in Example 3.

Example 90(1R)—N-(3,5-difluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

The title compound was synthesized using2-(4-amino-2,6-difluorophenyl)-2-methyl-1-(pyrrolidin-1-yl)propan-1-one,by the reaction and purification in the same manner as in Example 65.

Example 91((1R)-1-((4-tert-butyl-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)(oxo)acetic acid

The title compound was synthesized using 2-(tert-butoxy)-2-oxoaceticacid, by the reaction and purification in the same manner as in Example12.

Example 926-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-6-oxohexanoicacid

A solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(70 mg, 0.18 mmol), oxepane-2,7-dione (27.6 mg, 0.22 mmol) and TEA(0.030 mL, 0.22 mmol) in THF (2.0 mL) was stirred at room temperaturefor 5 hr, and the reaction mixture was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 10→50% ethyl acetate/hexane) togive the title compound (9.9 mg, 0.019 mmol, 10.65%) as a white solid.

MS(API): Calculated 518.6. Found 519.2 (M+H).

¹H NMR (300 MHz, DMSO-d): δ 0.29 (9H, s), 1.41-1.67 (4H, m), 2.12-2.31(1H, m), 2.36-2.61 (3H, m), 2.66-2.89 (1H, m), 3.00-3.19 (1H, m),3.43-3.60 (1H, m), 3.72 (3H, s), 3.95-4.11 (1H, m), 5.61 (1H, s), 6.82(2H, d, J=9.8 Hz), 7.19 (2H, d, J=9.8 Hz), 7.45 (1H, d, J=8.3 Hz), 10.74(1H, s), 11.97 (1H, s).

Example 93(2-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethoxy)aceticacid

The title compound was synthesized using 1,4-dioxane-2,6-dione, by thereaction and purification in the same manner as in Example 92.

Example 945-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-5-oxopentanoicacid

A solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(70 mg, 0.18 mmol), 4-methyldihydro-2H-pyran-2,6(3H)-dione (27.6 mg,0.22 mmol) and TEA (0.030 mL, 0.22 mmol) in THF (2.0 mL) was stirred atroom temperature for 3 hr, and the reaction mixture was concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (Diol, solvent gradient; 10→50% ethylacetate/hexane) to give the title compound (42.8 mg, 0.083 mmol, 46.0%)as a white solid.

MS(API): Calculated 518.6. Found 517.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ 0.30 (9H, s), 0.82-0.99 (3H, m), 2.04-2.20(1H, m), 2.21-2.41 (3H, m), 2.42-2.61 (1H, m), 2.75-2.89 (1H, m),3.03-3.21 (1H, m), 3.45-3.59 (1H, m), 3.73 (3H, s), 3.97-4.10 (1H, m),5.62 (1H, s), 6.78-6.85 (2H, m), 7.14-7.25 (2H, m), 7.46 (1H, d, J=9.4Hz), 10.77 (1H, s), 12.04 (1H, brs).

Example 955-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-5-oxopentanoicacid

A solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(70 mg, 0.18 mmol), 4,4-dimethyldihydro-2H-pyran-2,6(3H)-dione (30.6 mg,0.22 mmol) and TEA (0.030 mL, 0.22 mmol) in THF (2.0 mL) was stirred atroom temperature for 3 hr, and the reaction mixture was concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (Diol, solvent gradient; 10→950% ethylacetate/hexane) to give the title compound (46.8 mg, 0.088 mmol, 49.0%)as a white solid.

MS(API): Calculated 532.7. Found 531.0 (M−H).

¹H NMR (300 MHz, DMSO-d): δ 0.29 (9H, s), 1.09 (6H, d, J=1.1 Hz),2.25-2.44 (2H, m), 2.56-2.86 (2H, m), 3.04-3.19 (1H, m), 3.45-3.61 (1H,m), 3.73 (3H, s), 3.96-4.15 (2H, m), 5.57-5.70 (1H, m), 6.76-6.89 (2H,m), 7.14-7.25 (2H, m), 7.45 (1H, d, J=9.1 Hz), 10.77 (1H, s), 11.93 (1H,brs).

Example 96(1R)-2-(amino(oxo)acetyl)-N-(4-tert-butyl-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

The title compound was synthesized by subjecting the compound of Example91 to amidation.

Example 97(1R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

Diethyl malonate (44.8 g, 280 mmol) was added to a suspension of sodiumhydride (60% oil, 28.0 g, 700 mmol) in THF (280 mL) at 0° C., and themixture was stirred at room temperature for 1 hr. Then,1,2,3-trifluoro-5-nitrobenzene (24.79 g, 140 mmol) was added thereto at0° C., and the mixture was stirred at room temperature for 2 hr. To thereaction mixture was added aqueous ammonium chloride solution, and themixture was extracted twice with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure to give diethyl2,6-difluoro-4-nitrophenylmalonate (42 g) as a colorless oil.

A solution of thus-obtained diethyl 2,6-difluoro-4-nitrophenylmalonate(42 g) in a mixed solvent of acetic acid (200 mL), water (150 mL) andconc. sulfuric acid (50 mL) was heated under reflux for 18 hr, and thereaction mixture was concentrated under reduced pressure. To the residuewas added water, and the mixture was extracted twice with ethyl acetate.The organic layer was back extracted with 10% aqueous sodium carbonatesolution, and the aqueous layer was acidified with 2N hydrochloric acid.The precipitate was collected by filtration to give2-(2,6-difluoro-4-nitrophenyl)acetic acid (27.90 g, 128 mmol, 92.0%) aswhite crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 3.79 (2H, s), 7.81-8.24 (2H, m), 12.93 (1H,brs).

(Step 2)

A solution of 2-(2,6-difluoro-4-nitrophenyl)acetic acid (27.90 g, 128.5mmol) and conc. sulfuric acid (1.0 mL) in MeOH (260 mL) was heated underreflux for 18 hr. The reaction mixture was neutralized with aqueoussodium hydrogen carbonate solution, and ethyl acetate and water wereadded thereto. The organic layer was dried over magnesium sulfate, andthe solvent was evaporated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (solvent gradient;0→100% ethyl acetate/hexane) to give methyl2-(2,6-difluoro-4-nitrophenyl)acetate (28.71 g, 128.5 mmol, 97.0%) as ayellow solid.

¹H NMR (300 MHz, CDCl₃): δ 3.75 (3H, s), 3.80 (2H, s), 7.80-7.85 (2H,m).

(Step 3)

To a solution of methyl 2-(2,6-difluoro-4-nitrophenyl)acetate (10.7 g,50.20 mmol) and iodomethane (12.55 mL, 200.79 mmol) in DMF (100 mL) wasadded sodium hydride (60% oil, 5.02 g, 125.49 mmol) at 0° C., and themixture was stirred at 0° C. for 4 hr. To the reaction mixture was addedaqueous ammonium chloride solution, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 5→20% ethyl acetate/hexane) to givemethyl 2-(2,6-difluoro-4-nitrophenyl)-2-methylpropanoate (12.10 g, 50.2mmol, 100%) as yellow crystals.

(Step 4)

A solution of methyl 2-(2,6-difluoro-4-nitrophenyl)-2-methylpropanoate(3.2 g, 12.35 mmol) and 10% palladium-carbon (1.314 g, 0.617 mmol, 50%wet) in MeOH (30 mL) was stirred overnight under hydrogen atmosphere (1atm) at room temperature. The catalyst was removed by filtration, andthe filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 3→50% ethyl acetate/hexane) to give methyl2-(4-amino-2,6-difluorophenyl)-2-methylpropanoate (2.87 g, 12.52 mmol,101%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.59 (6H, t, J=1.7 Hz), 3.69 (3H, s), 3.77(2H, brs), 6.00-6.25 (2H, m).

(Step 5)

To a solution of methyl2-(4-amino-2,6-difluorophenyl)-2-methylpropanoate (2.8 g, 12.22 mmol)and α-chloro-4-methoxytoluene (3.48 mL, 25.65 mmol) in DMF (50 mL) wasadded sodium hydride (60% oil, 1.075 g, 26.87 mmol) at 0° C., and themixture was stirred at 0° C. for 4 hr. To the reaction mixture was addedaqueous ammonium chloride solution, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 3→50% ethyl acetate/hexane) to givemethyl2-(4-(bis(4-methoxybenzyl)amino)-2,6-difluorophenyl)-2-methylpropanoate(2.470 g, 5.26 mmol, 43.1%) as an orange oil.

(Step 6)

To a solution of methyl2-(4-(bis(4-methoxybenzyl)amino)-2,6-difluorophenyl)-2-methylpropanoate(2.17 g, 4.62 mmol) in THF (30 mL) was added 1M DIBAL-H/THF solution(13.87 mL, 13.87 mmol) at 0° C., and the mixture was stirred at 0° C.for 5 hr. 1M DIBAL-H/THF solution (1.0 mL, 1.0 mmol) was again addedthereto at 0° C., and the mixture was stirred at 0° C. for 1.5 hr. Tothe reaction mixture were added IN hydrochloric acid and water, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 3→50% ethylacetate/hexane), and then silica gel column chromatography (NH, solventgradient; 3→50% ethyl acetate/hexane) to give2-(4-(bis(4-methoxybenzyl)amino)-2,6-difluorophenyl)-2-methylpropan-1-ol(1.310 g, 2.97 mmol, 64.2%) as a colorless oil.

(Step 7)

To a solution of2-(4-(bis(4-methoxybenzyl)amino)-2,6-difluorophenyl)-2-methylpropan-1-ol(1.31 g, 2.97 mmol) and iodomethane (0.278 mL, 4.45 mmol) in DMF (10 mL)was added sodium hydride (60% oil, 0.154 g, 3.86 mmol) at 0° C., and themixture was stirred at 0° C. for 4 hr. To the reaction mixture was addedwater, and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 3→940%ethyl acetate/hexane) to give3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)aniline(1.000 g, 2.195 mmol, 74.0%) as a yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 1.37-1.42 (6H, m), 3.33 (3H, s), 3.50 (2H,s), 3.80 (6H, s), 4.46 (4H, s), 6.08-6.24 (2H, m), 6.86 (4H, d, J=8.3Hz), 7.11 (4H, d, J=8.7 Hz).

(Step 8)

A solution of3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)aniline(1 g, 2.20 mmol) in TFA (10 mL) was stirred at room temperature for 1hr. The reaction mixture was concentrated under reduced pressure, and tothe obtained residue was added ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 3→50% ethylacetate/hexane) to give3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)aniline (0.470 g, 2.184mmol, 99%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 1.40 (6H, t, J=2.5 Hz), 3.32 (3H, s), 3.50(2H, s), 3.69 (2H, brs), 6.07-6.16 (2H, m).

(Step 9)

To a solution of2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (671 mg, 2.18 mmol),3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)aniline (470 mg, 2.18mmol), DIEA (1.907 mL, 10.92 mmol) and DMAP (267 mg, 2.18 mmol) in ethylacetate (30 mL) was added T3P (3.85 mL, 6.55 mmol) at room temperature,and the mixture was stirred overnight at 60° C. To the reaction mixturewas added water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 5→60% ethyl acetate/hexane), and then silica gel columnchromatography (NH, solvent gradient; 5→60% ethyl acetate/hexane), andthe precipitate was washed with ethyl acetate/hexane to give tert-butyl1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(440 mg, 0.872 mmol, 39.9%.) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 1.42 (6H, t, J=2.3 Hz), 1.51 (9H, s),2.72-2.99 (2H, m), 3.30 (3H, s), 3.46-3.75 (4H, m), 3.80 (3H, s), 5.57(1H, brs), 6.73 (1H, s), 6.81 (1H, dd, J=8.5, 2.8 Hz), 6.94-7.11 (2H,m), 7.10-7.20 (1H, m), 8.93 (1H, brs).

(Step 10)

tert-Butyl1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(440 mg) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(200 mg, >99.9% ee) as a white solid.

purification condition by chiral column chromatography

column: CHIRALCEL OD (NF001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 11)

To a solution of tert-butyl(R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(200 mg, 0.40 mmol) in ethyl acetate (3 mL) was added 4M hydrogenchloride/ethyl acetate (4 mL) at room temperature, and the mixture wasstirred overnight. The reaction mixture was concentrated under reducedpressure to give(R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (175 mg, 0.397 mmol, 100%) as white crystals.

(Step 12)

A solution of(R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (50 mg, 0.11 mmol), DIEA (0.048 mL, 0.27 mmol),3-hydroxy-1,2-oxazole-5-carboxylic acid (17.56 mg, 0.14 mmol) and COMU(58.3 mg, 0.14 mmol) in DMF (2 mL) was stirred at 0° C. for 1 hr. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 20→100% ethyl acetate/hexane,0→20% MeOH/ethyl acetate) to give the title compound (37.0 mg, 0.072mmol, 63.3%) as brown crystals.

MS(API): Calculated 515.5. Found 514.0 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ 1.36 (6H, s), 2.79-2.95 (1H, m), 3.07-3.23(4H, m), 3.45 (2H, s), 3.64-3.82 (4H, m), 3.93-4.25 (1H, m), 5.54-5.70(1H, m), 6.58 (1H, s), 6.76-6.76-6.94 (2H, m), 7.19 (2H, d, J=13.2 Hz),7.44-7.58 (1H, m), 10.80 (1H, s), 11.81 (1H, brs).

[α]_(D) ²⁵ −19.4 (c 0.2520, MeOH

Example 98(1R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

A solution of(R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (48 mg, 0.11 mmol), DIEA (0.046 mL, 0.26 mmol),2-(3-hydroxy-1,2-oxazol-5-yl)acetic acid (18.69 mg, 0.13 mmol) and HATU(49.7 mg, 0.13 mmol) in DMF (2 mL) was stirred at 0° C. for 2 hr. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 20→100% ethyl acetate/hexane,0→90% MeOH/ethyl acetate), and crystallized from ethyl acetate/hexane togive the title compound (31.0 mg, 0.059 mmol, 53.8%) as white crystals.

MS(API): Calculated 529.5. Found 530.1 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ 1.35 (6H, s), 2.75-2.90 (1H, m), 3.04-3.16(1H, m), 3.19 (3H, s), 3.44 (2H, s), 3.51-3.63 (1H, m), 3.73 (3H, s),3.88-4.17 (3H, m), 5.62 (1H, s), 5.91 (1H, s), 6.75-6.91 (2H, m), 7.17(2H, d, J=13.2 Hz), 7.47 (1H, d, J=9.4 Hz), 10.68 (1H, s), 11.11 (1H,brs).

Example 99(1R)—N-(3-fluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

The title compound was synthesized using2-(4-amino-2-fluorophenyl)-2-methyl-1-(pyrrolidin-1-yl)propan-1-one, bythe reaction and purification in the same manner as in Example 3.

Example 100(1R)—N-(6-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-5-fluoropyridin-3-yl)-6-methoxy-2-(3,3,3-trifluoropropanoyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

The title compound was synthesized using6-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-5-fluoropyridin-3-amineand 3,3,3-trifluoro-propionic acid, by the reaction and purification inthe same manner as in Example 65.

Example 101(1R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

To a solution of 1-ethyl 2-tert-butyl6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (5 g, 15.56mmol), DIEA (5.43 mL, 31.12 mmol) and DMAP (0.190 g, 1.56 mmol) in THF(30 mL) was added1,1,1-trifluoro-N-phenyl-N-(trifluoromethyl)sulfonylmethanesulfonamide(8.34 g, 23.34 mmol) at room temperature, and the mixture was stirred atroom temperature for 3 hr. To the reaction mixture was added water, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 3→50% ethylacetate/hexane), and then silica gel column chromatography (NH, solventgradient; 3→50% ethyl acetate/hexane) to give 1-ethyl 2-tert-butyl6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate(7.44 g, 16.41 mmol, 105%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.21-1.31 (3H, m), 1.45-1.53 (9H, m),2.82-2.99 (2H, m), 3.60-3.77 (1H, m), 3.80-3.99 (1H, m), 4.18 (2H, q,J=7.2 Hz), 5.28-5.69 (1H, m), 7.01-7.19 (2H, m), 7.60 (1H, dd, J=8.7,3.8 Hz).

(Step 2)

A solution of 1-ethyl 2-tert-butyl6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate(7.44 g, 16.41 mmol), Pd(PPh₃)₄ (0.948 g, 0.82 mmol) and zinc cyanide(2.119 g, 18.05 mmol) in DMF (100 mL) was stirred overnight at 100° C.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 30→60% ethyl acetate/hexane) to give1-ethyl 2-tert-butyl6-cyano-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (4.92 g, 14.89mmol, 91%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.18-1.33 (3H, m), 1.42-1.53 (9H, m),2.78-3.03 (2H, m), 3.62-3.78 (1H, m), 3.80-3.99 (1H, m), 4.18 (2H, q,J=7.1 Hz), 5.38-5.71 (1H, m), 7.40-7.55 (2H, m), 7.58-7.69 (1H, m).

(Step 3)

To a mixture of Raney-nickel catalyst (NDHT-90) (0.5 g) and 1-ethyl2-tert-butyl 6-cyano-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (0.5g, 1.51 mmol) in a mixed solvent of acetic acid (5.00 mL), pyridine (10mL) and water (5 mL) was added sodium hypophosphite monohydrate (2.5 g,23.59 mmol) at room temperature under argon gas atmosphere, and themixture was stirred at 60° C. for 3 hr, and then overnight at 100° C.The catalyst was removed by filtration with ethyl acetate, and thefiltrate was washed with aqueous ammonium chloride solution, aqueoussodium hydrogen carbonate solution and brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent gradient; 5→70% ethyl acetate/hexane) to give 1-ethyl2-tert-butyl 6-formyl-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate(0.430 g, 1.290 mmol, 85%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.26 (3H, t, J=7.2 Hz), 1.45-1.53 (9H, m),2.80-3.13 (2H, m), 3.63-3.97 (2H, m), 4.18 (2H, q, J=7.2 Hz), 5.44-5.72(1H, m), 7.61-7.80 (3H, m), 9.99 (1H, s).

(Step 4)

To a solution of 1-ethyl 2-tert-butyl6-formyl-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (430 mg, 1.29mmol) in MeOH (10 mL) was added sodium borohydride (24.40 mg, 0.64 mmol)at 0° C., and the mixture was stirred at room temperature for 20 min. Tothe reaction mixture was added aqueous ammonium chloride solution, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure to give 1-ethyl 2-tert-butyl6-(hydroxymethyl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (390 mg,1.163 mmol, 90%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.23-1.30 (3H, m), 1.37-1.51 (9H, m), 1.67(1H, brs), 2.70-3.05 (2H, m), 3.66-3.84 (2H, m), 4.11-4.21 (2H, m), 4.67(2H, s), 5.28-5.64 (1H, m), 7.13-7.25 (2H, m), 7.44-7.54 (1H, m).

(Step 5)

To a solution of 1-ethyl 2-tert-butyl6-(hydroxymethyl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (390 mg,1.16 mmol) and methanesulfonyl chloride (0.135 mL, 1.74 mmol) in THF (10mL) was added TEA (0.243 mL, 1.74 mmol) at 0° C., and the mixture wasstirred at room temperature for 1 hr. To the reaction mixture was addedwater, and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure to give 1-ethyl2-tert-butyl6-(((methylsulfonyl)oxy)methyl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate(500 mg, 1.209 mmol, 104%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.20-1.30 (3H, m), 1.44-1.51 (9H, m),2.78-3.05 (5H, m), 3.70-3.92 (2H, m), 4.16 (2H, q, J=7.2 Hz), 5.20 (2H,s), 5.37-5.65 (1H, m), 7.20-7.30 (2H, m), 7.49-7.59 (1H, m).

(Step 6)

To a solution of 1-ethyl 2-tert-butyl6-(((methylsulfonyl)oxy)methyl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate(500 mg, 1.21 mmol) in MeOH (5 mL) was added TEA (0.337 mL, 2.42 mmol)at room temperature, and the mixture was stirred at 70° C. for 2 hr. Thereaction mixture was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(solvent gradient; 3→60% ethyl acetate/hexane) to give 1-ethyl2-tert-butyl6-(methoxymethyl)-3,4-dihydroisoquinoline-1,2(H)-dicarboxylate (169 mg,0.484 mmol, 40.0%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.20-1.30 (3H, m), 1.43-1.53 (9H, m),2.73-3.06 (2H, m), 3.40 (3H, s), 3.67-3.84 (2H, m), 4.14 (2H, q, J=7.2Hz), 4.42 (2H, s), 5.22-5.64 (1H, m), 7.05-7.22 (2H, m), 7.42-7.56 (1H,m).

(Step 7)

To a solution of 1-ethyl 2-tert-butyl6-(methoxymethyl)-3,4-dihydroisoquinoioline-1,2(1H)-dicarboxylate (160mg, 0.46 mmol) in a mixed solvent of MeOH (5 mL), THF (5.00 mL) andwater (5.00 mL) was added lithium hydroxide (65.8 mg, 2.75 mmol) at roomtemperature, and the mixture was stirred at 60° C. for 1 hr. Thereaction mixture was concentrated under reduced pressure. To theobtained residue was added ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure to give2-(tert-butoxycarbonyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (148 mg, 0.461 mmol, 101%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.35-1.57 (9H, m), 2.77-3.02 (2H, m), 3.39(3H, s), 3.60-3.90 (2H, m), 4.42 (2H, s), 5.23-5.66 (1H, m), 7.07-7.22(2H, m), 7.45 (1H, d, J=7.6 Hz) (The exchangeable 1H was not observed).

(Step 8)

To a solution of2-(tert-butoxycarbonyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (148 mg, 0.46 mmol), 3-fluoro-4-(trimethylsilyl)aniline (84 mg,0.46 mmol), DIEA (0.402 mL, 2.30 mmol) and DMAP (56.3 mg, 0.46 mmol) inethyl acetate (5 mL) was added T3P (0.813 mL, 1.38 mmol) at roomtemperature, and the mixture was stirred at 60° C. for 48 hr. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(solvent gradient; 2→40% ethyl acetate/hexane) to give tert-butyl1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(178 mg, 0.366 mmol, 79%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.27 (9H, s), 1.52 (9H, s), 2.80-3.01 (2H,m), 3.39 (3H, s), 3.49-3.85 (2H, m), 4.44 (2H, s), 5.64 (1H, brs), 7.10(1H, d, J=7.6 Hz), 7.21 (2H, d, J=10.6 Hz), 7.26-7.32 (2H, m), 7.38 (1H,dd, J=10.6, 1.9 Hz), 8.95 (1H, brs).

(Step 9)

Cooled TFA (2 mL) was added to tert-butyl1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(178 mg, 0.37 mmol) at 0° C., and the mixture was stirred at roomtemperature for 2 min.

The reaction mixture was added to ice and aqueous sodium hydrogencarbonate solution. Then, the mixture was extracted with ethyl acetate.The organic layer was washed with brine, and dried over sodium sulfate,and the solvent was evaporated under reduced pressure. To the obtainedresidue was added cooled TFA (2 mL) at 0° C., and the mixture wasstirred at room temperature for 7 min. The reaction mixture was added toice and aqueous sodium hydrogen carbonate solution. Then, the mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, and dried over sodium sulfate, and the solvent was evaporatedunder reduced pressure to giveN-(3-fluoro-4-(trimethylsilyl)phenyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(141 mg) as a crude product. The total amount thereof was used for thenext step.

(Step 10)

A solution ofN-(3-fluoro-4-(trimethylsilyl)phenyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(141 mg) obtained in Step 9, DIEA (0.076 mL, 0.44 mmol),2-(3-hydroxy-1,2-oxazol-5-yl)acetic acid (62.6 mg, 0.44 mmol) and HATU(166 mg, 0.44 mmol) in DMF (4 mL) was stirred at 0° C. for 1 hr. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 20→100% ethyl acetate/hexane,0→10% MeOH/ethyl acetate), and crystallized from ethyl acetate/hexane togiveN-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(2-(3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(96 mg, 0.188 mmol, 51.4%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 0.18-0.29 (9H, m), 2.87 (1H, d, J=15.1 Hz),3.13 (1H, d, J=4.5 Hz), 3.27 (3H, s), 3.64 (1H, t, J=8.1 Hz), 3.89-4.16(3H, m), 4.36 (2H, s), 5.75 (1H, s), 5.91 (1H, s), 7.13-7.23 (2H, m),7.24-7.38 (2H, m), 7.45 (1H, d, J=11.3 Hz), 7.55 (1H, d, J=7.6 Hz),10.70 (1H, s), 11.11 (1H, s).

(Step 11)

N-(3-Fluoro-4-(trimethylsilyl)phenyl)-2-(2-(3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(96 mg) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give the titlecompound (45 mg, >99.8% ee) as a white solid.

MS(API): Calculated 511.6. Found 512.1 (M+H).

purification condition by chiral column chromatography

column: CHIRALPAK IA (QK001) 50 mmID×500 mmL

solvent: hexane/EtOH/acetic acid=500/500/1

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

[α]_(D) ²⁵ +16.8 (c 0.2505, MeOH)

The compounds described in Examples 1 to 101 are as follows (Table1-1-Table 1-11).

TABLE 1-1 EXAM- PLE IUPACNAME Structure ADDITIVE MS  12-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-N-(4-(trimethylsilyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

466.1 (M + H)  2 6-methoxy-2-((6-oxo-1,6-dihydropyridin-3-yl)carbonyl)-N-(4-(trimethylsilyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

474.2 (M − H)  3 N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

484.2 (M + H)  4 N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-methoxy-2-((6-oxo-1,6-dihydropyridin-3-yl)carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

492.2 (M − H)  5 4-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-8-methoxy-N-(4-(trimethylsilyl)phenyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-carboxamide

482.1 (M + H)  6 8-methoxy-4-((6-oxo-1,6-dihydropyridin-3-yl)carbonyl)-N-(4-(trimethylsilyl)phenyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-carboxamide

490.2 (M − H)  7 (1R)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

484.2 (M + H)  8 (1R)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-methoxy-2-((6-oxo-1,6-dihydropyridin-3- yl)carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

492.2 (M − H)  9 N-(4-tert-butyl-3-fluorophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

468.2 (M + H) 10 N-(4-tert-butyl-3-chlorophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

482.0 (M − H)

TABLE 1-2 EXAMPLE IUPACNAME Structure ADDITIVE MS 11N-(7-fluoro-1,1-dimethyl-2,3-dihydro- 1H-inden-5-yl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy- 1,2,3,4-tetrahydroisoquinoline-1-carboxamide

480.1 (M + H) 12 N-(4-tert-butyl-3,5-difluorophenyl)-2-((3-hydroxy-1,2-oxazol-5- yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

486.1 (M + H) 13 (1R)-N-(4-tert-butyl-3-fluorophenyl)-2-((3-hydroxy-1,2-oxazol-5- yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

468.2 (M + H) 14 (1S)-N-(4-tert-butyl-3-fluorophenyl)-2-((3-hydroxy-1,2-oxazol-5- yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

468.1 (M + H) 15 (1R)-N-(4-tert-butyl-3-fluorophenyl)-2-((2,4-dioxo-1,3-thiazolidin-5- yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

512.0 (M − H) 16 (1R)-N-(4-tert-butyl-3-fluorophenyl)-2-((2,6-dioxopiperidin-4-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline- 1-carboxamide

508.2 (M − H) 17 (1R)-N¹-(4-tert-butyl-3-fluorophenyl)-6-methoxy-N²-(pyridazin-3-yl)-3,4- dihydroisoquinoline-1,2(1H)-dicarboxamide

478.1 (M + H) 18 (1R)-N-(4-tert-butyl-3-fluorophenyl)-2-((2,5-dioxoimidazolidin-4- yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

495.0 (M − H) 19 (1R)-N-(4-tert-butyl-3-fluorophenyl)-2-((2,4-dioxoimidazolidin-4- yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

497.2 (M + H) 20 (1R)-N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-((5-oxopyrrolidin-3-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline- 1-carboxamide

482.2 (M + H)

TABLE 1-3 EXAMPLE IUPACNAME Structure ADDITIVE MS 21(1R)-N¹-(4-tert-butyl-3-fluorophenyl)-6-methoxy-N²-(1-methyl-1H-pyrazol- 3-yl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxamide

480.2 (M + H) 22 (1R)-N-(4-tert-butyl-3-fluorophenyl)-2-((5,5-dimethyl-2,4-dioxo-1,3- oxazolidin-3-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1- carboxamide

524.1 (M − H) 23 (1R)-N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-((2-oxoimidazolidin-1-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline- 1-carboxamide

483.1 (M + H) 24 (1R)-N-(4-tert-butyl-3-fluorophenyl)-2-((2,4-dioxo-3,4-dihydropyrimidin- 1(2H)-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1- carboxamide

507.1 (M − H) 25 (1R)-N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-(((3S)-5-oxopyrrolidin- 3-yl)carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-carboxamide

466.0 (M − H) 26 (1R)-N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-(((3R)-5-oxopyrrolidin- 3-yl)carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-carboxamide

466.0 (M − H) 27 (1R)-N-(4-tert-butyl-3-fluorophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)- 6-methoxy-1,2,3,4-tetrahydro-isoquinoline-1-carboxamide

480.0 (M − H) 28 (1R)-N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-((5-methyl-1,3,4- oxadiazol-2-yl)acetyl)-1,2,3,4-tetra-hydroisoquinoline-1-carboxamide

481.1 (M + H) 29 (1R)-N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-((6-oxopyrimidin- 1(6H)-yl)acetyl)-1,2,3,4-tetrahydro-isoquinoline-1-carboxamide

491.1 (M − H) 30 (1R)-N-(4-tert-butyl-3-fluorophenyl)-2-(3-hydroxypropanoyl)-6-methoxy- 1,2,3,4-tetrahydroisoquinoline-1-carboxamide

427.1 (M − H)

TABLE 1-4 EXAMPLE IUPACNAME Structure ADDITIVE MS 31(1R)-N-(4-tert-butyl-3-fluorophenyl)- 6-methoxy-2-(3-(methyl-sulfonyl)propanoyl)-1,2,3,4-tetrahydro- isoquinoline-1-carboxamide

491.1 (M + H) 32 (1R)-N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-((6-methoxypyridin-3- yl)acetyl)-1,2,3,4-tetrahydro-isoquinoline-1-carboxamide

506.2 (M + H) 33 (1R)-N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-((6-oxo-1,6-dihydropyridin- 3-yl)acetyl)-1,2,3,4-tetrahydro-isoquinoline-1-carboxamide

492.2 (M + H) 34 4-((1R)-1-((4-tert-butyl-3-fluoro-phenyl)carbamoyl)-6-methoxy-3,4- dihydroisoquinolin-2(1H)-yl)-4-oxobutanoic acid

455.1 (M − H) 35 N-(4-tert-butyl-3-fluorophenyl)-4-((3-hydroxy-1,2-oxazol-5- yl)carbonyl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-5- carboxamide

484.1 (M + H) 36 N-(3,5-difluoro-4-(trimethyl-silyl)phenyl)-4-((3-hydroxy-1,2- oxazol-5-yl)carbonyl)-8-methoxy-2,3,4,5-tetrahydro-1,4- benzoxazepine-5-carboxamide

518.1 (M + H) 37 ethyl 2-(2-fluoro-4-(((2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy- 1,2,3,4-tetrahydroisoquinolin-1-yl)carbonyl)amino)phenyl)-2- methylpropanoate

524.1 (M − H) 38 N-(4-tert-butyl-3-fluorophenyl)-6-(1H-indazol-1-ylacetyl)-1-methyl-2- oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-5-carboxamide

516.3 (M + H) 39 N-(3,5-difluoro-4-(trimethyl-silyl)phenyl)-6-(1H-indazol-1- ylacetyl)-1-methyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6- naphthyridine-5-carboxamide

550.2 (M + H) 40 (1R)-N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-(2H-tetrazol-5-ylacetyl)- 1,2,3,4-tetrahydroisoquinoline-1-carboxamide

465.0 (M − H)

TABLE 1-5 EXAMPLE IUPACNAME Structure ADDITIVE MS 41N-(4-tert-butyl-3-fluorophenyl)-6- ((3-hydroxy-1,2-oxazol-5-yl)acetyl)-2-methoxy-5,6,7,8- tetrahydro-1,6-naphthyridine-5-carboxamide

483.1 (M + H) 42 N-(4-(1-(ethylamino)-2-methyl-1-oxopropan-2-yl)-3-fluorophenyl)- 6-methoxy-2-propionyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

468.2 (M − H) 43 (1R)-N-(4-tert-butyl-3,5-difluoro-phenyl)-2-((3-hydroxy-1,2-oxazol-5- yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

497.8 (M − H) 44 (1R)-N-(4-tert-butyl-3-fluorophenyl)-2-((1,1-dioxidotetrahydro-2H- thiopyran-4-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1- carboxamide

529.0 (M − H) 45 (1R)-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2- ((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydro- isoquinoline-1-carboxamide

492.1 (M − H) 46 N-(3-fluoro-4-(2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2- yl)phenyl)-6-methoxy-2-propionyl-1,2,3,4-tetrahydroisoquinoline-1- carboxamide

481.1 (M + H) 47 (1R)-N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-propionyl-1,2,3,4- tetrahydroisoquinoline-1- carboxamide

411.1 (M − H) 48 (1R)-N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-(3,3,3-trifluoro- propanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-carboxamide

467.1 (M + H) 49 N-(4-tert-butyl-3-fluorophenyl)-4-((3-hydroxy-1,2-oxazol-5-yl)acetyl)- 8-methoxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-carboxamide

498.1 (M + H) 50 N-(3,5-difluoro-4-(trimethyl-silyl)phenyl)-4-((3-hydroxy-1,2- oxazol-5-yl)acetyl)-8-methoxy-2,3,4,5-tetrahydro-1,4- benzoxazepine-5-carboxamide

530.0 (M − H)

TABLE 1-6 EXAMPLE IUPACNAME Structure ADDITIVE MS 51N-(4-tert-butyl-3-(difluoro- methoxy)phenyl)-2-((3-hydroxy-1,2-oxazol-5- yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoqinoline-1- carboxamide

528.0 (M − H) 52 N-(4-tert-butyl-3-(2,2-difluoro- ethoxy)phenyl)-2-((3-hydroxy-1,2-oxazol-5- yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoqinoline-1- carboxamide

542.1 (M − H) 53 N-(4-tert-butyl-3-cyanophenyl)-2-((3-hydroxy-1,2-oxazol-5- yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoqinoline-1- carboxamide

487.1 (M − H) 54 N-(4-tert-butyl-3-fluorophenyl)-6-ethoxy-2-((3-hydroxy-1,2- oxazol-5-yl)acetyl)-1,2,3,4-tetrahydroisoqinoline-1- carboxamide

494.1 (M − H) 55 6-ethoxy-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden- 5-yl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-1,2,3,4- tetrahydroisoquinoline-1- carboxamide

506.0 (M − H) 56 (5R)-N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-4-((3-hydroxy-1,2-oxazol-5- yl)acetyl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzoxaze- pine-5-carboxamide

532.1 (M + H) 57 (5S)-N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-4-((3-hydroxy-1,2-oxazol-5- yl)acetyl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzoxaze- pine-5-carboxamide

532.1 (M + H) 58 (5R)-N-(4-tert-butyl-3,5-difluorophenyl)-4-((3-hydroxy- 1,2-oxazol-5-yl)carbonyl)-8-methoxy-2,3,4,5-tetrahydro- 1,4-benzoxazepine-5- carboxamide

502.1 (M + H) 59 (5S)-N-(4-tert-butyl-3,5-difluorophenyl)-4-((3-hydroxy- 1,2-oxazol-5-yl)carbonyl)-8-methoxy-2,3,4,5-tetrahydro- 1,4-benzoxazepine-5- carboxamide

502.1 (M + H) 60 (5R)-N-(4-tert-butyl-3,5-difluorophenyl)-4-((3-hydroxy- 1,2-oxazol-5-yl)acetyl)-8-methoxy-2,3,4,5-tetrahydro- 1,4-benzoxazepine-5- carboxamide

516.2 (M + H)

TABLE 1-7 EXAMPLE IUPACNAME Structure ADDITIVE MS 61N-(4-(1-(cyclopropylamino)-2- methyl-1-oxopropan-2-yl)-3-fluorophenyl)-6-methoxy-2- (3,3,3-trifluoropropanoyl)-1,2,3,4-tetrahydroisoquinoline- 1-carboxamide

536.2 (M + H) 62 N-(3-fluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan- 2-yl)phenyl)-6-methoxy-2-(3,3,3-trifluoropropanoyl)- 1,2,3,4-tetrahydroisoquinoline-1-carboxamide

550.2 (M + H) 63 (1R)-N-(7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)-2-(3-(3-hydroxy- 1,2-oxazol-5-yl)propanoyl)-6-methoxy-1,2,3,4-tetrahydro- isoquinoline-1-carboxamide

508.2 (M + H) 65 (1R)-N-(4-tert-butyl-3- cyanophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6- methoxy-1,2,3,4-tetrahydro-isoquinoline-1-carboxamide

487.0 (M − H) 66 (1R)-6-ethoxy-N-(7-fluoro- 1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-((3- hydroxy-1,2-oxazol-5- yl)acetyl)-1,2,3,4-tetrahydroisoquinoline- 1-carboxamide

508.2 (M + H) 67 (1R)-N-(4-tert-butyl-3-fluoro- phenyl)-6-ethoxy-2-((3-hydroxy-1,2-oxazol-5- yl)acetyl)-1,2,3,4-tetrahydro-isoquinoline-1-carboxamide

496.1 (M + H) 68 (1R)-N-(7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)-2-((3-hydroxy- 1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetra- hydroisoquinoline-1- carboxamide

480.1 (M + H) 69 (1R)-N-(3-fluoro-4-(1- methoxy-2-methylpropan-2-yl)phenyl)-2-((3-hydroxy- 1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydro- isoquinoline-1-carboxamide

498.0 (M + H) 70 (1R)-N-(3-fluoro-4-(1- methoxy-2-methylpropan-2-yl)phenyl)-2-((3-hydroxy- 1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydro- isoquinoline-1-carboxamide

512.1 (M + H)

TABLE 1-8 EXAMPLE IUPACNAME Structure ADDITIVE MS 71N-(4-(2,2-dimethylpropyl)- 3-fluorophenyl)- 2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4- tetrahydroisoqinoline-1- carboxamide

496.2 (M + H) 72 (1R)-N-(3-cyano-4- (trimethylsilyl)phenyl)-2-((3-hydroxy-1,2-oxazol-5- yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoqinoline-1- carboxamide

505.1 (M + H) 73 (1R)-N-(3-fluoro-4- (trimethylsilyl)phenyl)-2-((3-hydroxy-1,2-oxazol-5- yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoqinoline-1- carboxamide

498.1 (M + H) 74 (1R)-N-(4-fluoro-3,3- dimethyl-2,3-dihydro-1-benzofuran-6-yl)-2- ((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4- tetrahydroisoqinoline-1- carboxamide

496.1 (M + H) 75 (1R)-N-(4-(1-(2,2-difluoro- ethoxy)-2-methylpropan-2-yl)-3-fluorophenyl)- 2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4- tetrahydroisoqinoline-1- carboxamide

546.0 (M + H) 77 (5R)-N-(4-tert-butyl-3- fluorophenyl)-6-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-2- methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine- 5-carboxamide

469.1 (M + H) 78 (5R)-N-(4-tert-butyl-3- fluorophenyl)-6-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-2- methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine- 5-carboxamide

483.1 (M + H) 79 (5R)-N-(3-fluoro-4- (trimethylsilyl)phenyl)-6-((3-hydroxy-1,2-oxazol-5- yl)carbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6- naphthyridine-5- carboxamide

485.2 (M + H) 80 (5R)-N-(3-fluoro-4- (trimethylsilyl)phenyl)-6-((3-hydroxy-1,2-oxazol-5- yl)acetyl)-2-methoxy- 5,6,7,8-tetrahydro-1,6-naphthyridine-5- carboxamide

499.1 (M + H)

TABLE 1-9 EXAMPLE IUPACNAME Structure ADDITIVE MS 81(1R)-N-(4-fluoro-3,3-dimethyl- 2,3-dihydro-1-benzofuran-6-yl)-2-((3-hydroxy-1,2-oxazol- 5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline- 1-carboxamide

480.0 (M − H) 82 5-((1R)-1-((3,5-difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4- dihydroisoquinolin-2(1H)- yl)-5-oxopentanoicacid

503.0 (M − H) 83 4-((1R)-1-((3,5-difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4- dihydroisoquinolin-2(1H)- yl)-4-oxobutanoicacid

489.1 (M − H) 84 (1R)-N-(4-tert-butyl-3,5- difluorophenyl)-2-(cyanoacetyl)-6-methoxy- 1,2,3,4-tetrahydroisoquinoline- 1-carboxamide

440.0 (M − H) 85 (1R)-N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-2-((3-hydroxy-1,2-oxazol-5- yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1- carboxamide

516.1 (M + H) 86 5-((1R)-1-((4-(ethyl(dimethyl) silyl)-3,5-difluoro-phenyl)carbamoyl)-6-methoxy- 3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoic acid

519.1 (M + H) 87 4-((1R)-1-((4-(ethyl(dimethyl) silyl)-3,5-difluoro-phenyl)carbamoyl)-6-methoxy- 3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutanoic acid

503.0 (M − H) 88 (1R)-N-(4-(ethyl(dimethyl)silyl)-3,5-difluorophenyl)-2- ((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4- tetrahydroisoquinoline-1- carboxamide

530.1 (M + H) 89 (1R)-N-(3,5-difluoro-4-(2- methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)- 2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy- 1,2,3,4-tetrahydroisoquinoline- 1-carboxamide

569.1 (M + H) 90 (1R)-N-(3,5-difluoro-4-(2- methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)- 2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy- 1,2,3,4-tetrahydroisoquinoline- 1-carboxamide

583.2 (M + H)

TABLE 1-10 EXAMPLE IUPACNAME Structure ADDITIVE MS  91((1R)-1-((4-tert-butyl-3,5- difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydro- isoquinolin-2(1H)-yl) (oxo)acetic acid

445.1 (M − H)  92 6-((1R)-1-((3,5-difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-methoxy- 3,4-dihydroisoquinolin- 2(1H)-yl)-6-oxohenanoicacid

519.2 (M + H)  93 (2-((1R)-1-((3,5-difluoro- 4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy- 3,4-dihydroisoquinolin- 2(1H)-yl)-2-oxoethoxy)acetic acid

505.0 (M − H)  94 5-((1R)-1-((3,5-difluoro- 4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy- 3,4-dihydroisoquinolin- 2(1H)-yl)-3-methyl-5-oxopentanoic acid

517.1 (M − H)  95 5-((1R)-1-((3,5-difluoro- 4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy- 3,4-dihydroisoquinolin- 2(1H)-yl)-3,3-dimethyl-5-oxopentanoic acid

531.0 (M − H)  96 (1R)-2-(amino(oxo)acetyl)- N-(4-tert-butyl-3,5-difluorophenyl)-6- methoxy-1,2,3,4- tetrahydroisoquinoline-1-carboxamide

446.0 (M + H)  97 (1R)-N-(3,5-difluoro-4- (1-methoxy-2-methyl-propan-2-yl)phenyl)- 2-((3-hydroxy-1,2-oxazol- 5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydro- isoquinoline-1- carboxamide

514.0 (M − H)  98 (1R)-N-(3,5-difluoro-4- (1-methoxy-2-methyl-propan-2-yl)phenyl)- 2-((3-hydroxy-1,2-oxazol- 5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydro- isoquinoline-1- carboxamide

530.1 (M + H)  99 N-(3-fluoro-4-(2- methyl-1-oxo-1-(pyrrolidin-1-yl)propan- 2-yl)phenyl)-2-((3- hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy- 1,2,3,4-tetrahydro- isoquinoline-1- carboxamide

551.2 (M + H) 100 (1R)-N-(6-(1-(2,2- difluoroethoxy)-2-methylpropan-2-yl)-5- fluoropyridin-3-yl)-6- methoxy-2-(3,3,3-trifluoropropanoyl)-1,2,3,4- tetrahydroisoquinoline- 1-carboxamide

548.1 (M + H)

TABLE 1-11 EXAMPLE IUPACNAME Structure ADDITIVE MS 101(1R)-N-(3-fluoro-4- (trimethylsilyl)phenyl)- 2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6- (methoxymethyl)-1,2,3,4- tetrahydroisoquinoline-1-carboxamide

512.1 (M + H)

Example 102(1R)—N-(6-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-5-fluoropyridin-3-yl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

The title compound was synthesized using6-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-5-fluoropyridin-3-amineand 2-(3-hydroxyisoxazol-5-yl)acetic acid, by the reaction andpurification in the same manner as in Example 65.

¹H NMR (300 MHz, DMSO-d₆): δ 1.30 (6H, s), 2.84 (1H, d, J=17.0 Hz), 3.10(1H, brs), 3.62 (3H, td, J=15.1, 3.8 Hz), 3.73 (5H, s), 3.86-4.15 (3H,m), 5.68 (1H, s), 5.79-6.28 (1H, m), 5.91 (1H, s), 6.78-6.88 (2H, m),7.49 (1H, d, J=9.8 Hz), 7.87 (1H, d, J=14.7 Hz), 8.45 (1H, s), 10.84(1H, s), 11.10 (1H, s).

Example 103(1R)-2-(cyanoacetyl)-N-(3,5-difluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

8M aqueous sodium hydroxide solution (10 mL, 80.00 mmol) was added to amixture of methyl 2-(2,6-difluoro-4-nitrophenyl)-2-methylpropanoate (2g, 7.72 mmol) in ethanol (30 mL) at room temperature, and the mixturewas stirred for 3 hr. The pH of the mixture was adjusted to 4 with 1Nhydrochloric acid at room temperature, ethyl acetate was added thereto,and the organic layer was separated. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure to give2-(2,6-difluoro-4-nitrophenyl)-2-methylpropanoic acid (1.650 g, 6.73mmol, 87%) as a pale yellow solid.

¹H NMR (300 MHz, DMSO-d): δ 1.58 (6H, t, J=1.9 Hz), 7.88-8.17 (2H, m),12.80 (1H, brs) (The peak derived from COOH was not observed)

(Step 2)

HATU (3.07 g, 8.08 mmol) was added to a solution of DIEA (2.351 mL,13.46 mmol), pyrrolidine (0.674 mL, 8.08 mmol) and2-(2,6-difluoro-4-nitrophenyl)-2-methylpropanoic acid (1.65 g, 6.73mmol) in DMF (10 mL) at room temperature, and the mixture was stirred atroom temperature. To the reaction mixture was added saturated aqueoussodium hydrogen carbonate, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 20→70% ethyl acetate/hexane) to give2-(2,6-difluoro-4-nitrophenyl)-2-methyl-1-(pyrrolidin-1-yl)propan-1-one(1.940 g, 6.50 mmol, 97%) as a yellow oil.

¹H NMR (300 MHz, DMSO-d₆): δ 1.56 (6H, t, J=2.1 Hz), 1.61-1.74 (4H, m),2.76 (2H, brs), 3.33 (2H, brs), 7.78-8.25 (2H, m).

(Step 3)

A solution of2-(2,6-difluoro-4-nitrophenyl)-2-methyl-1-(pyrrolidin-1-yl)propan-1-one(1.94 g, 6.50 mmol) and 10% palladium-carbon (200 mg, 1.88 mmol, 50%wet) in MeOH (30 mL) was stirred overnight under hydrogen atmosphere (1atm) at room temperature. The catalyst was removed by filtration, andthe filtrate was concentrated under reduced pressure to give2-(4-amino-2,6-difluorophenyl)-2-methyl-1-(pyrrolidin-1-yl)propan-1-one(1650 mg, 6.15 mmol, 95%) as a yellow oil.

¹H NMR (300 MHz, DMSO-d₆): δ 1.42 (6H, s), 1.65 (4H, brs), 2.86 (2H,brs), 3.29 (2H, brs), 5.61 (2H, s), 6.03-6.22 (2H, m).

(Step 4)

T3P (5.49 mL, 9.22 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (1.89 g, 6.15 mmol),2-(4-amino-2,6-difluorophenyl)-2-methyl-1-(pyrrolidin-1-yl)propan-1-one(1.65 g, 6.15 mmol), DIEA (5.37 mL, 30.75 mmol) and DMAP (0.826 g, 6.76mmol) in ethyl acetate (100 mL) at room temperature, and the mixture wasstirred at 70° C. for 15 hr. To the reaction mixture was added water(350 mL), and the mixture was extracted twice with ethyl acetate. Theorganic layer was washed with aqueous sodium hydrogen carbonate solutionand brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 50→100% ethylacetate/hexane) to give crude tert-butyl1-((3,5-difluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(3.16 g, 5.67 mmol, 92%) as a yellow oil.

¹H NMR (300 MHz, DMSO-d₆): δ 1.21-1.70 (19H, m), 2.75 (3H, dd, J=10.8,4.3 Hz), 3.08 (1H, d, J=10.6 Hz), 3.22-3.50 (3H, m), 3.73 (3H, s), 3.97(1H, brs), 5.21-5.45 (1H, m), 6.75-6.90 (2H, m), 7.27 (2H, d, J=12.1Hz), 7.45 (1H, d, J=7.9 Hz), 10.33-10.88 (1H, m).

(Step 5)

The crude tert-butyl1-((3,5-difluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.98 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((3,5-difluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(450 mg, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-1-((3,5-difluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(460 mg, >99% ee).

purification condition by chiral column chromatography

column: CHIRALCEL OD (NL001) 50 mmID×500 mmL

solvent: hexane/EtOH=850/150

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 6)

4N Hydrogen chloride/ethyl acetate (5 mL, 20.00 mmol) was added totert-butyl(R)-1-((3,5-difluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(450 mg, 0.81 mmol), and the mixture was stirred at room temperature for3 hr. The reaction mixture was concentrated under reduced pressure togive(R)—N-(3,5-difluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (380 mg, 0.769 mmol, 95%) as a white solid.

MS(API): Calculated 493.7. Found 456.2 (M−HCl−H).

(Step 7)

HATU (41.6 mg, 0.11 mmol) was added to a solution of DIEA (0.048 mL,0.27 mmol), 2-cyanoacetic acid (9.30 mg, 0.11 mmol) and(R)—N-(3,5-difluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (45 mg, 0.09 mmol) in DMF (2 mL) at room temperature, andthe mixture was stirred overnight at room temperature. To the reactionmixture was added aqueous sodium hydrogen carbonate solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 0→20% MeOH/ethylacetate) to give the title compound (19.00 mg, 0.036 mmol, 39.8%) as awhite solid.

¹H NMR (300 MHz, DMSO-d₆): δ 1.47 (6H, s), 1.64 (4H, brs), 2.69-2.92(3H, m), 3.02-3.18 (1H, m), 3.37-3.50 (3H, m), 3.73 (3H, s), 3.89-4.03(1H, m), 4.08-4.42 (2H, m), 5.61 (1H, s), 6.77-6.91 (2H, m), 7.25 (2H,d, J=12.1 Hz), 7.40-7.54 (1H, m), 10.77 (1H, s).

Example 104(1R)—N-(3,5-difluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-6-methoxy-2-(3,3,3-trifluoropropanoyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

HATU (41.6 mg, 0.11 mmol) was added to a solution of DIEA (0.048 mL,0.27 mmol), 3,3,3-trifluoropropanoic acid (14.00 mg, 0.11 mmol) and(R)—N-(3,5-difluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (45 mg, 0.09 mmol) in DMF (2 mL) at room temperature, andthe mixture was stirred overnight at room temperature. To the reactionmixture was added aqueous sodium hydrogen carbonate solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 20→80% ethylacetate/hexane) to give the title compound (30.0 mg, 0.053 mmol, 58.0%)as a white solid.

¹H NMR (300 MHz, DMSO-d): δ 1.47 (6H, s), 1.64 (4H, brs), 2.67-2.94 (3H,m), 3.05-3.20 (1H, m), 3.23-3.30 (2H, m), 3.39-3.56 (1H, m), 3.73 (3H,s), 3.76-3.86 (1H, m), 3.87-3.98 (1H, m), 3.98-4.14 (1H, m), 5.62 (1H,s), 6.80-6.89 (2H, m), 7.25 (2H, d, J=12.1 Hz), 7.48 (1H, d, J=9.1 Hz),10.78 (1H, s).

Example 105(1R)—N-(3,5-difluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-6-methoxy-2-(pyridin-3-ylacetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

HATU (41.6 mg, 0.11 mmol) was added to a solution of DIEA (0.048 mL,0.27 mmol), 2-(pyridin-3-yl)acetic acid hydrochloride (18.98 mg, 0.11mmol) and(R)—N-(3,5-difluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (45 mg, 0.09 mmol) in DMF (2 mL) at room temperature, andthe mixture was stirred overnight at room temperature. To the reactionmixture was added aqueous sodium hydrogen carbonate solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 0→25% MeOH/ethylacetate) to give the title compound (33.0 mg, 0.057 mmol, 62.8%) as awhite solid.

¹H NMR (300 MHz, DMSO-d): δ 1.46 (6H, s), 1.63 (4H, brs), 2.67-2.90 (3H,m), 3.15 (1H, s), 3.22-3.30 (2H, m), 3.59 (1H, brs), 3.73 (3H, s),3.80-4.03 (2H, m), 4.08-4.21 (1H, m), 5.62 (1H, s), 6.79-6.88 (2H, m),7.24 (2H, d, J=12.1 Hz), 7.33 (1H, dd, J=7.9, 4.9 Hz), 7.47 (1H, d,J=9.1 Hz), 7.63 (1H, d, J=7.6 Hz), 8.33-8.54 (2H, m), 10.73 (1H, s).

Example 106(1R)—N-(3,5-difluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-6-methoxy-2-((5-methyl-,3,4-oxadiazol-2-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

HATU (41.6 mg, 0.11 mmol) was added to a solution of DIEA (0.048 mL,0.27 mmol), lithium 2-(5-methyl-1,3,4-oxadiazol-2-yl)acetate (16.18 mg,0.11 mmol) and(R)—N-(3,5-difluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (45 mg, 0.09 mmol) in DMF (2 mL) at room temperature, andthe mixture was stirred overnight at room temperature. To the reactionmixture was added aqueous sodium hydrogen carbonate solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 0→15% MeOH/ethylacetate) to give the title compound (28.0 mg, 0.048 mmol, 52.8%) as awhite solid.

¹H NMR (300 MHz, DMSO-d₆): δ 1.47 (6H, s), 1.63 (4H, brs), 2.47 (3H, s),2.70-2.95 (3H, m), 3.07-3.23 (1H, m), 3.24-3.30 (2H, m), 3.46-3.65 (1H,m), 3.74 (3H, s), 4.05-4.19 (1H, m), 4.22-4.48 (2H, m), 5.58 (1H, s),6.79-6.92 (2H, m), 7.24 (2H, d, J=12.1 Hz), 7.48 (1H, d, J=8.3 Hz),10.71 (1H, s).

Example 107(1R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

To a solution of2-(tert-butoxycarbonyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (1.54 g, 4.79 mmol), 3-fluoro-4-(trimethylsilyl)aniline (0.878 g,4.79 mmol), DIEA (4.18 mL, 23.96 mmol) and DMAP (0.644 g, 5.27 mmol) inethyl acetate (40 mL) was added T3P (8.46 mL, 14.38 mmol) at roomtemperature, and the mixture was stirred at 60° C. for 2 hr. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 2→40% ethyl acetate/hexane) to givetert-butyl1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.830 g, 3.76 mmol, 78%) as white crystals.

MS(API): Calculated 486.7. Found 387.3 (M+H-Boc).

(Step 2)

tert-Butyl1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.80 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.81 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.83 g, >99% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALPAK AD (NF001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

Cooled TFA (12 mL) was added to a solution of tert-butyl(R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.83 g, 1.71 mmol) at 0° C., and the mixture was stirred at 0° C. for 3min. The reaction mixture was added to ice and aqueous sodium hydrogencarbonate solution, and potassium carbonate was added thereto until thepH of the mixture became 8. Then, the mixture was extracted with ethylacetate to give(R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(0.600 g, 1.552 mmol, 91%) as a colorless oil.

MS(API): Calculated 386.5. Found 387.3 (M+H).

(Step 4)

To a solution of(R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(40 mg, 0.10 mmol), DIEA (0.022 mL, 0.12 mmol) and3-hydroxyisoxazole-5-carboxylic acid (16.03 mg, 0.12 mmol) in DMF (2 mL)was added COMU (53.2 mg, 0.12 mmol) at 0° C., and the mixture wasstirred at 0° C. for 1 hr. To the reaction mixture was added water, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (Diol, solvent gradient; 80→100% ethylacetate/hexane, 0→10% MeOH/ethyl acetate) to give the title compound(44.0 mg, 0.088 mmol, 85%) as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆): δ 0.25 (9H, s), 2.84-2.98 (1H, m), 3.08-3.23(1H, m), 3.28 (3H, s), 3.79 (1H, ddd, J=12.5, 8.5, 4.0 Hz), 4.11-4.26(1H, m), 4.38 (2H, s), 5.78 (1H, s), 6.58 (1H, s), 7.19-7.25 (2H, m),7.27-7.40 (2H, m), 7.41-7.51 (1H, m), 7.59 (1H, d, J=8.7 Hz), 10.83 (1H,s), 11.84 (1H, brs).

[α]_(D) ²⁵ −5.9 (c 0.2500, MeOH)

Example 108((2-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)(methyl)amino)aceticacid

A solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(50 mg, 0.13 mmol), 4-methylmorpholine-2,6-dione (19.84 mg, 0.15 mmol)and TEA (0.021 mL, 0.15 mmol) in THF (2.0 mL) was stirred overnight atroom temperature. The reaction mixture was concentrated under reducedpressure, and the obtained residue was purified by silica gel columnchromatography (solvent; ethyl acetate) to give the title compound (51.2mg, 0.099 mmol, 77%) as a white powder.

¹H NMR (300 MHz, DMSO-d₆): δ 0.30 (9H, s), 2.38 (3H, s), 2.72-2.89 (1H,m), 2.89-3.00 (1H, m), 3.01-3.20 (2H, m), 3.35-3.49 (1H, m), 3.51-3.66(3H, m), 3.73 (3H, s), 4.06-4.22 (1H, m), 5.60 (1H, s), 6.72-6.86 (2H,m), 7.13-7.26 (2H, m), 7.39-7.50 (1H, m), 10.81 (1H, s).

Example 1095-((1R)-1-((4-tert-butyl-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

A solution of(R)—N-(4-(tert-butyl)-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(100 mg, 0.27 mmol), dihydro-2H-pyran-2,6(3H)-dione (45.7 mg, 0.40 mmol)and TEA (0.093 mL, 0.67 mmol) in THF (2.0 mL) was stirred at roomtemperature for 3 hr. The reaction mixture was concentrated underreduced pressure, and the obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 50→100% ethyl acetate/hexane)to give the title compound (52.8 mg, 0.108 mmol, 40.5%) as a whitepowder.

¹H NMR (300 MHz, DMSO-d₆): δ 0.30 (9H, s), 1.63-1.82 (2H, m), 2.16-2.32(3H, m), 2.35-2.48 (1H, m), 2.51-2.63 (1H, m), 2.70-2.88 (1H, m),3.04-3.20 (1H, m), 3.42-3.58 (1H, m), 3.73 (3H, s), 5.58-5.65 (1H, m),6.76-6.87 (2H, m), 7.13-7.26 (2H, m), 7.46 (1H, d, J=9.4 Hz), 10.76 (1H,s), 12.03 (1H, brs).

[α]_(D) ²⁵ −5.7 (c 0.252, MeOH)

Example 1105-((1R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

A solution of(R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(208 mg, 0.54 mmol), TEA (0.076 mL, 0.54 mmol) anddihydro-2H-pyran-2,6(3H)-dione (61.4 mg, 0.54 mmol) in THF (4 mL) wasstirred at 60° C. for 4 hr, and the reaction mixture was concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 10→100% ethyl acetate/hexane)to give the title compound (223 mg, 0.445 mmol, 83%) as a white powder.

¹H NMR (300 MHz, DMSO-d₆): δ 0.19-0.29 (9H, m), 1.64-1.83 (1H, m),2.22-2.33 (2H, m), 2.42 (3H, s), 2.46-2.62 (2H, m), 2.75-2.93 (1H, m),3.03-3.20 (1H, m), 3.26 (2H, s), 3.48-3.64 (1H, m), 4.03 (1H, q, J=6.9Hz), 4.36 (2H, s), 5.74 (1H, s), 7.11-7.22 (2H, m), 7.27-7.38 (2H, m),7.45 (1H, d, J=11.0 Hz), 7.53 (1H, d, J=7.6 Hz), 10.66 (1H, s).

[α]_(D) ²⁵ +2.2 (C 0.2500, MeOH)

Example 111(5R)—N-(4-(ethyl(dimethyl)silyl)-3,5-difluorophenyl)-6-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(Step 1)

To a solution of6-(tert-butoxycarbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylicacid (1.141 g, 3.7 mmol), 4-(ethyldimethylsilyl)-3,5-difluoroaniline(0.797 g, 3.70 mmol), DIEA (3.22 mL, 18.50 mmol) and DMAP (0.497 g, 4.07mmol) in ethyl acetate (27 mL) was added T3P (3.30 mL, 5.55 mmol) atroom temperature, and the mixture was stirred at 65° C. for 15 hr. Tothe reaction mixture was added water, and the mixture was extractedthree times with ethyl acetate. The organic layer was washed with 10%aqueous citric acid solution, sodium hydrogen carbonate solution, waterand brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The precipitate was collected byfiltration with cooled hexane to give tert-butyl5-((4-(ethyldimethylsilyl)-3,5-difluorophenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.42 g, 2.81 mmol, 76%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 0.31 (6H, t, J=1.5 Hz), 0.77-0.98 (5H, m),1.53 (9H, s), 2.82-3.03 (2H, m), 3.44 (1H, brs), 3.92 (3H, s), 4.00-4.10(1H, m), 5.58 (1H, brs), 6.65 (1H, d, J=8.3 Hz), 6.99-7.07 (2H, m), 7.46(1H, brs), 9.03 (1H, brs).

(Step 2)

tert-Butyl5-((4-(ethyldimethylsilyl)-3,5-difluorophenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.41 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-5-((4-(ethyldimethylsilyl)-3,5-difluorophenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(620 mg, >99% ee), and the fraction having a longer retention wasconcentrated to give tert-butyl(S)-5-((4-(ethyldimethylsilyl)-3,5-difluorophenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(635 mg, >99% ee), each as white crystals.

purification condition by chiral column chromatography

column: CHIRALPAK IA (QK001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

Cooled TFA (8.5 mL) was added to tert-butyl(R)-5-((4-(ethyldimethylsilyl)-3,5-difluorophenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(617 mg, 1.22 mmol) at room temperature, and the mixture was stirred atroom temperature for 3 min. The reaction mixture was added to ice andaqueous sodium hydrogen carbonate solution, and potassium carbonate wasadded thereto until the pH of the mixture became 8. Then, the mixturewas extracted three times with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The precipitate was washed withIPE/hexane to give(R)—N-(4-(ethyldimethylsilyl)-3,5-difluorophenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(478 mg, 1.179 mmol, 97%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 0.31 (6H, t, J=1.5 Hz), 0.74-0.84 (2H, m),0.93 (3H, t), 1.66 (1H, brs), 2.74-2.98 (2H, m), 3.11-3.30 (2H, m), 3.90(3H, s), 4.58 (1H, s), 6.61 (1H, d, J=8.3 Hz), 7.05-7.13 (2H, m), 7.81(1H, d, J=8.7 Hz), 9.59 (1H, s).

(Step 4)

HATU (215 mg, 0.56 mmol) was added to a solution of(R)—N-(4-(ethyldimethylsilyl)-3,5-difluorophenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(176 mg, 0.43 mmol), 3-hydroxyisoxazole-5-carboxylic acid (67.2 mg, 0.52mmol) and DIEA (151 μL, 0.87 mmol) in DMF (2.2 mL), and the mixture wasstirred at room temperature for 15 hr. To the reaction mixture was addedwater, and the mixture was extracted three times with ethyl acetate. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (Diol, solventgradient; 15→85% ethyl acetate/hexane) to give the title compound (175.7mg, 0.340 mmol, 78%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.31 (6H, s), 0.74-0.84 (2H, m), 0.93 (3H,t), 2.84 (1H, s), 3.02-3.11 (1H, m), 3.16-3.29 (1H, m), 3.78-3.89 (1H,m), 3.94 (3H, s), 4.32-4.42 (1H, m), 5.95 (1H, s), 6.60 (1H, s), 6.68(1H, d, J=8.7 Hz), 7.01-7.10 (2H, m), 7.41 (1H, d, J=8.7 Hz), 9.19 (1H,s).

Example 112(5S)—N-(4-(ethyl(dimethyl)silyl)-3,5-difluorophenyl)-6-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide

The title compound was synthesized using tert-butyl(S)-5-((4-(ethyldimethylsilyl)-3,5-difluorophenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate,by the reaction and purification in the same manner as in Example 111.

¹H NMR (300 MHz, CDCl₃): δ 0.31 (6H, s), 0.74-0.84 (2H, m), 0.93 (3H,t), 2.84 (1H, s), 3.02-3.11 (1H, m), 3.16-3.29 (1H, m), 3.78-3.90 (1H,m), 3.94 (3H, s), 4.32-4.42 (1H, m), 5.95 (1H, s), 6.60 (1H, s), 6.69(1H, d, J=8.7 Hz), 7.06 (2H, d, J=8.7 Hz), 7.41 (1H, d, J=8.7 Hz), 9.17(1H, s).

Example 113(5R)—N-(4-(ethyl(dimethyl)silyl)-3,5-difluorophenyl)-6-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide

HATU (216 mg, 0.57 mmol) was added to a solution of(R)—N-(4-(ethyldimethylsilyl)-3,5-difluorophenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(177 mg, 0.44 mmol), 2-(3-hydroxyisoxazol-5-yl)acetic acid (75.0 mg,0.52 mmol) and DIEA (152 μL, 0.87 mmol) in DMF (2.2 mL) at roomtemperature, and the mixture was stirred at room temperature for 15 hr.To the reaction mixture was added water, and the mixture was extractedthree times with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 15→85% ethyl acetate/hexane),and the precipitate was washed with IPE/hexane to give the titlecompound (87.5 mg, 0.165 mmol, 37.8%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 0.27 (6H, s), 0.70-0.81 (2H, m), 0.91 (3H,t), 2.91-3.02 (2H, m), 3.18 (1H, dt, J=16.6, 4.9 Hz), 3.88 (3H, s),3.90-4.07 (4H, m), 5.95 (1H, s), 5.97 (1H, s), 6.64 (1H, d, J=8.7 Hz),6.84-6.92 (2H, m), 7.44 (1H, d, J=8.3 Hz), 9.38 (1H, s).

Example 1145-((5R)-5-((4-(ethyl(dimethyl)silyl)-3,5-difluorophenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-oxopentanoicacid

Dihydro-2H-pyran-2,6(3H)-dione (35.2 mg, 0.31 mmol) was added to asolution of(R)—N-(4-(ethyldimethylsilyl)-3,5-difluorophenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(119 mg, 0.29 mmol) and TEA (45 μL, 0.32 mmol) in THF (2.5 mL) at roomtemperature, and the mixture was stirred at room temperature for 4 hr.To the reaction mixture was added water, and 2N hydrochloric acid wasadded thereto until the pH of the mixture became 4. Then, the mixturewas extracted three times with a mixed solvent of ethyl acetate/THF(3:1). The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography (Diol,solvent gradient; 20→100% ethyl acetate/hexane) to give the titlecompound (64.6 mg, 0.124 mmol, 42.4%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 0.26 (6H, d, J=1.5 Hz), 0.69-0.79 (2H, m),0.90 (3H, t), 1.58 (1H, brs), 2.05-2.19 (2H, m), 2.44 (2H, t, J=6.2 Hz),2.56 (1H, ddd, J=14.7, 8.7, 5.7 Hz), 2.88-3.10 (2H, m), 3.25 (1H, dt,J=16.1, 5.5 Hz), 3.92 (3H, s), 3.94-4.00 (1H, m), 4.06 (1H, td, J=8.4,4.0 Hz), 5.85 (1H, s), 6.63 (1H, d, J=8.7 Hz), 6.77-6.85 (2H, m), 7.70(1H, d, J=8.3 Hz), 9.84 (1H, s).

Example 115(5R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(Step 1)

T3P (4.89 mL, 8.22 mmol) was added to a solution of6-(tert-butoxycarbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylicacid (1.69 g, 5.48 mmol),7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine (0.982 g, 5.48 mmol),DIEA (4.77 mL, 27.41 mmol) and DMAP (0.737 g, 6.03 mmol) in ethylacetate (40 mL), and the mixture was stirred at 65° C. for 15 hr. Thereaction mixture was washed with 10% aqueous citric acid solution,aqueous sodium hydrogen carbonate solution and brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained precipitate was washed with hexane to givetert-butyl5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(2.09 g, 4.45 mmol, 81-) as grayish white crystals.

¹H NMR (300 MHz, CDCl₃): δ 1.34 (6H, s), 1.53 (9H, s), 1.91 (2H, t,J=7.4 Hz), 2.83-3.01 (4H, m), 3.45 (1H, brs), 3.91 (3H, s), 4.06 (1H,dt, J=13.2, 4.9 Hz), 5.56 (1H, brs), 6.64 (1H, d, J=8.3 Hz), 7.05-7.12(2H, m), 7.48 (1H, brs), 8.70 (1H, brs).

(Step 2)

tert-Butyl5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(2.09 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(960 mg, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(920 mg, >99% ee), each as a grayish white solid.

purification condition by chiral column chromatography

column: CHIRALPAK IA (QK001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

Cooled TFA (13 mL) was added to tert-butyl(R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(957 mg, 2.04 mmol) at room temperature, and the mixture was stirred atroom temperature for 20 min. The reaction mixture was added to ice andaqueous sodium hydrogen carbonate solution, and aqueous sodium hydrogencarbonate solution was added thereto until the pH of the mixture became8. Then, the mixture was extracted three times with ethyl acetate. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure to give(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(732 mg, 1.981 mmol, 97%) as a grayish white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.34 (6H, s), 1.69 (1H, brs), 1.91 (2H, t,J=7.4 Hz), 2.73-2.98 (4H, m), 3.12-3.28 (2H, m), 3.90 (3H, s), 4.57 (1H,s), 6.60 (1H, d, J=8.7 Hz), 7.11-7.17 (2H, m), 7.84 (1H, d, J=8.7 Hz),9.41 (1H, s).

(Step 4)

HATU (214 mg, 0.56 mmol) was added to a solution of(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(160 mg, 0.43 mmol), 3-hydroxyisoxazole-5-carboxylic acid (67.1 mg, 0.52mmol) and DIEA (151 μL, 0.87 mmol) in DMF (2.2 mL) at room temperature,and the mixture was stirred at room temperature for 15 hr. To thereaction mixture was added water, and the mixture was extracted threetimes with ethyl acetate. The organic layer was washed with brine, anddried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 20→90% ethyl acetate/hexane) togive the title compound (142.9 mg, 0.297 mmol, 68.7%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 1.34 (6H, s), 1.91 (2H, t, J=7.4 Hz), 2.83(1H, s), 2.87 (2H, t, J=7.4 Hz), 2.99-3.09 (1H, m), 3.15-3.29 (1H, m),3.76-3.88 (1H, m), 3.93 (3H, s), 4.31-4.41 (1H, m), 5.95 (1H, s), 6.57(1H, s), 6.68 (1H, d, J=8.3 Hz), 7.08 (1H, s), 7.15 (1H, d, J=11.3 Hz),7.41 (1H, d, J=8.7 Hz), 8.90 (1H, s).

[α]_(D) ²⁵ +89.6 (c 0.2525, MeOH)

Example 116(5S)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide

The title compound was synthesized using tert-butyl(S)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate,by the reaction and purification in the same manner as in Steps 3 to 4of Example 115.

¹H NMR (300 MHz, CDCl₃): δ 1.33 (6H, s), 1.91 (2H, t, J=7.4 Hz),2.83-2.92 (3H, m), 3.00-3.09 (1H, m), 3.15-3.28 (1H, m), 3.79-3.90 (1H,m), 3.93 (3H, s), 4.30-4.39 (1H, m), 5.95 (1H, s), 6.57 (1H, s), 6.67(1H, d, J=8.7 Hz), 7.08 (1H, s), 7.14 (1H, d, J=11.7 Hz), 7.42 (1H, d,J=8.7 Hz), 8.94 (1H, s).

Example 117(5R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide

HATU (214 mg, 0.56 mmol) was added to a solution of (R)—N-(7-fluoro-,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(160 mg, 0.43 mmol), 2-(3-hydroxyisoxazol-5-yl)acetic acid (74.4 mg,0.52 mmol) and DIEA (151 μL, 0.87 mmol) in DMF (2.2 mL) at roomtemperature, and the mixture was stirred at room temperature for 15 hr.To the reaction mixture was added water, and the mixture was extractedthree times with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 15→85% ethyl acetate/hexane),and the precipitate was washed with IPE/hexane to give the titlecompound (97.6 mg, 0.197 mmol, 45.6%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 1.30 (6H, s), 1.87 (2H, t, J=7.4 Hz), 2.81(2H, t, J=7.4 Hz), 2.88-3.01 (2H, m), 3.11 (1H, dt), 3.89 (3H, s),3.91-3.98 (4H, m), 5.96 (2H, s), 6.64 (1H, d, J=8.3 Hz), 6.92 (1H, s),7.05 (1H, d, J=11.7 Hz), 7.44 (1H, d, J=8.3 Hz), 9.00 (1H, s).

[α]_(D) ²⁵ +113.5 (c 0.2505, MeOH)

Example 1185-((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-oxopentanoicacid

Dihydro-2H-pyran-2,6(3H)-dione (51.9 mg, 0.45 mmol) was added to asolution of(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(160 mg, 0.43 mmol) and TEA (66 μL, 0.47 mmol) in THF (3.8 mL) at roomtemperature, and the mixture was stirred at room temperature for 4 hr.The reaction mixture was poured into water, and 2N hydrochloric acid wasadded thereto until the pH of the mixture became 4. The mixture wasextracted three times with a mixed solvent of ethyl acetate/THF (3:1).The organic layer was washed with water and brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 20→100% ethyl acetate/hexane) togive the title compound (80.1 mg, 0.166 mmol, 38%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.28 (6H, d, J=1.9 Hz), 1.85 (2H, t, J=7.4Hz), 2.02-2.16 (3H, m), 2.45 (2H, t, J=6.4 Hz), 2.57 (1H, dt, J=15.0,7.4 Hz), 2.73-2.91 (3H, m), 2.96-3.20 (2H, m), 3.91 (3H, s), 3.94-4.00(2H, m), 5.95 (1H, s), 6.63 (1H, d, J=8.3 Hz), 6.90 (1H, s), 7.03 (1H,d, J=12.1 Hz), 7.61 (1H, d, J=8.7 Hz), 9.41 (1H, s).

[α]_(D) ²⁵ +102.5 (c 0.2525, MeOH)

Example 1195-((1R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

The title compound was synthesized using(R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride and dihydro-2H-pyran-2,6(3H)-dione, by the reaction andpurification in the same manner as in Example 109.

¹H NMR (300 MHz, DMSO-d₆): δ 1.35 (6H, s), 1.63-1.83 (1H, m), 2.16-2.34(3H, m), 2.35-2.62 (2H, m), 2.69-2.89 (1H, m), 3.04-3.17 (1H, m), 3.31(3H, s), 3.39-3.57 (3H, m), 3.73 (3H, s), 3.92-4.09 (1H, m), 5.53-5.65(1H, m), 6.72-6.89 (2H, m), 7.07-7.26 (2H, m), 7.45 (1H, d, J=9.4 Hz),10.63 (1H, s), 12.04 (1H, brs).

Example 120(2S)-5-((1R)-1-((4-tert-butyl-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy-5-oxopentanoicacid

The title compound was synthesized using(R)—N-(4-(tert-butyl)-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride and (S)-5-(tert-butoxy)-4-hydroxy-5-oxopentanoic acid, bythe reaction and purification in the same manner as in Step 8 of Example1 and Step 7 of Example 1.

¹H NMR (300 MHz, CDCl₃): δ 1.38 (9H, s), 2.09-2.41 (2H, m), 2.60-2.94(4H, m), 3.06-3.21 (2H, m, J=2.0 Hz), 3.53-3.69 (1H, m), 3.80 (3H, s),3.84-3.97 (1H, m), 4.23-4.37 (1H, m), 5.89 (1H, s), 6.70-6.86 (2H, m),6.89-7.04 (2H, m), 7.22 (1H, d, J=8.7 Hz), 8.69 (1H, brs).

Example 121(1R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

T3P (10.38 mL, 17.64 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (1.89 g, 5.88 mmol), 3,5-difluoro-4-(trimethylsilyl)aniline (1.184g, 5.88 mmol), DIEA (5.14 mL, 29.41 mmol) and DMAP (0.718 g, 5.88 mmol)in ethyl acetate (5 mL), and the mixture was stirred at 60° C.overnight. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was crystallizedfrom ethyl acetate/hexane, and collected by filtration to givetert-butyl1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.The filtrate was concentrated under reduced pressure, and the residuewas purified by silica gel column chromatography (solvent gradient;3→40% ethyl acetate/hexane) to give tert-butyl1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.The both are combined to give a white solid (1.89 g, 63.7%).

¹H NMR (300 MHz, CDCl₃): δ 0.32 (9H, t, J=1.3 Hz), 1.52 (9H, s),2.71-2.99 (2H, m), 3.39 (3H, s), 3.50-3.81 (2H, m), 4.45 (2H, s), 5.61(1H, brs), 6.96-7.07 (2H, m), 7.17-7.25 (3H, m), 9.05 (1H, s).

(Step 2)

tert-Butyl1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.80 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.81 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.83 g, >99% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALPAK AD (NF001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

Cooled TFA (5 mL) was added to tert-butyl(R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(767 mg, 1.52 mmol), and the mixture was stirred under ice-cooling for 1hr. The reaction mixture was added to ice and aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with brine, and dried over sodium sulfate,and the solvent was evaporated under reduced pressure to give(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(228.6 mg, 0.602 mmol, 93%) as a pale yellow solid.

MS(API): Calculated 404.5. Found 403.2 (M−H).

(Step 4)

HATU (82 mg, 0.22 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(73 mg, 0.18 mmol), DIEA (0.038 mL, 0.22 mmol) and2-(3-hydroxyisoxazol-5-yl)acetic acid (31.0 mg, 0.22 mmol) in DMF (4 mL)at 0° C., and the mixture was stirred at 0° C. for 1 hr. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 5→100% ethyl acetate/hexane),and precipitated from ethyl acetate/hexane to give the title compound(48.0 mg, 0.091 mmol, 50.2%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 0.29 (9H, s), 2.76-2.95 (1H, m), 3.07-3.21(1H, m), 3.27 (3H, s), 3.54-3.70 (1H, m), 3.88-4.18 (3H, m), 4.37 (2H,s), 5.70 (1H, s), 5.91 (1H, s), 7.08-7.26 (4H, m), 7.53 (1H, d, J=7.6Hz), 10.87 (1H, s), 11.11 (1H, s).

Example 122(5R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(Step 1)

T3P (3.84 mL, 6.45 mmol) was added to a solution of6-(tert-butoxycarbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylicacid (1.326 g, 4.3 mmol), 3,5-difluoro-4-(trimethylsilyl)aniline (0.866g, 4.30 mmol), DIEA (3.74 mL, 21.50 mmol) and DMAP (0.578 g, 4.73 mmol)in ethyl acetate (31 mL) at room temperature, and the mixture wasstirred at 65° C. for 15 hr. To the reaction mixture was added water,and the mixture was extracted three times with ethyl acetate. Theorganic layer was washed with 10% aqueous citric acid solution, aqueoussodium hydrogen carbonate solution and brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theprecipitate was washed with cooled hexane to give tert-butyl5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.69 g, 3.44 mmol, 80%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 0.33 (9H, t, J=1.3 Hz), 1.54 (9H, s),2.83-3.02 (2H, m), 3.47 (1H, brs), 3.92 (3H, s), 3.98-4.09 (1H, m), 5.58(1H, brs), 6.64 (1H, d, J=8.3 Hz), 6.98-7.06 (2H, m), 7.46 (1H, brs),9.06 (1H, brs).

(Step 2)

tert-Butyl5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.69 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(750 mg, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(750 mg, >99% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALPAK AD (NF001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

Cooled TFA (10.5 mL) was added to tert-butyl(R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(747 mg, 1.52 mmol) at room temperature, and the mixture was stirred atroom temperature for 3 min. The reaction mixture was added to ice andaqueous sodium hydrogen carbonate solution, and aqueous sodium hydrogencarbonate solution was added thereto until the pH of the mixture became8. Then, the mixture was extracted three times with ethyl acetate. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure to give(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(567 mg, 1.448 mmol, 95%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.32 (9H, t, J=1.3 Hz), 1.66 (1H, brs),2.74-2.97 (2H, m), 3.11-3.29 (2H, m), 3.90 (3H, s), 4.58 (1H, s), 6.61(1H, d, J=8.3 Hz), 7.05-7.13 (2H, m), 7.80 (1H, d, J=8.3 Hz), 9.60 (1H,s).

(Step 4)

HATU (128 mg, 0.34 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(101 mg, 0.26 mmol), 3-hydroxyisoxazole-5-carboxylic acid (40.0 mg, 0.31mmol) and DIEA (90 μL, 0.52 mmol) in DMF (1.3 mL) at room temperature,and the mixture was stirred at room temperature for 15 hr. To thereaction mixture was added water, and the mixture was extracted threetimes with ethyl acetate. The organic layer was washed with brine, anddried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 15→485% ethyl acetate/hexane) togive the title compound (89.9 mg, 0.179 mmol, 69.3%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.33 (9H, s), 2.83 (1H, s), 3.01-3.11 (1H,m), 3.16-3.29 (1H, m), 3.76-3.87 (1H, m), 3.94 (3H, s), 4.32-4.42 (1H,m), 5.95 (1H, s), 6.60 (1H, s), 6.69 (1H, d, J=8.3 Hz), 7.06 (2H, d,J=8.7 Hz), 7.40 (1H, d, J=8.7 Hz), 9.13 (1H, s).

Example 123(5S)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide

The title compound was obtained using tert-butyl(S)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate,by the reaction and purification in the same manner as in Steps 3 to 4of Example 122.

¹H NMR (300 MHz, CDCl₃): δ 0.33 (9H, s), 2.83 (1H, s), 3.01-3.10 (1H,m), 3.17-3.30 (1H, m), 3.75-3.86 (1H, m), 3.94 (3H, s), 4.33-4.42 (1H,m), 5.95 (1H, s), 6.60 (1H, s), 6.69 (1H, d, J=8.7 Hz), 7.06 (2H, d,J=8.7 Hz), 7.40 (1H, d, J=8.7 Hz), 9.12 (1H, s).

Example 124(5R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide

HATU (129 mg, 0.34 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(102 mg, 0.26 mmol), 2-(3-hydroxyisoxazol-5-yl)acetic acid (44.7 mg,0.31 mmol) and DIEA (91 μL, 0.52 mmol) in DMF (1.3 mL) at roomtemperature, and the mixture was stirred at room temperature for 15 hr.To the reaction mixture was added water, and the mixture was extractedthree times with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 15→85% ethyl acetate/hexane),and crystallized from IPE/hexane to give the title compound (45.3 mg,0.088 mmol, 33.7%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.29 (9H, s), 2.88-3.01 (2H, m), 3.17 (1H,dt, J=16.5, 4.8 Hz), 3.88 (3H, s), 3.90-4.04 (4H, m), 5.95 (1H, s), 5.97(1H, s), 6.65 (1H, d, J=8.3 Hz), 6.88 (2H, d, J=8.7 Hz), 7.43 (1H, d,J=8.7 Hz), 9.31 (1H, s).

Example 1255-((5R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-oxopentanoicacid

Dihydro-2H-pyran-2,6(3H)-dione (34.6 mg, 0.30 mmol) was added to asolution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(113 mg, 0.29 mmol) and TEA (44 μL, 0.32 mmol) in THF (2.5 mL) at roomtemperature, and the mixture was stirred at room temperature for 15 hr.To the reaction mixture was added water, and 2N hydrochloric acid wasadded thereto until the pH of the mixture became 4. Then, the mixturewas extracted three times with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (Diol, solvent gradient; 20→100% ethylacetate/hexane) to give the title compound (66.5 mg, 0.132 mmol, 45.6%)as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.27 (9H, s), 2.06-2.20 (2H, m), 2.43 (2H,t), 2.55 (1H, ddd, J=14.5, 9.1, 5.5 Hz), 2.93-3.10 (2H, m), 3.22-3.34(1H, m), 3.92 (3H, s), 3.94-4.00 (1H, m), 4.07-4.17 (1H, m), 5.83 (1H,s), 6.63 (1H, d, J=8.3 Hz), 6.73-6.81 (2H, m), 7.74 (1H, d, J=8.7 Hz),9.94 (1H, s).

[α]_(D) ²⁵ +93.2 (c 0.2525, MeOH)

Example 126(5R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-ethoxy-6-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(Step 1)

Iodoethane (6.82 mL, 84.88 mmol) was added to a solution of 5-ethyl6-tert-butyl2-hydroxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (4.56 g,14.15 mmol) and silver(I) carbonate (5.07 g, 18.39 mmol) in THF (90 mL)at room temperature, and the mixture was stirred at room temperature for15 hr, and then at 50° C. for 4 hr. The insoluble substance was removedby filtration with ethyl acetate. The filtrate was concentrated underreduced pressure, and the obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 5→25% ethyl acetate/hexane) togive 5-ethyl 6-tert-butyl2-ethoxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (4.45 g,12.70 mmol, 90%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.22-1.30 (3H, m), 1.37 (3H, t, J=7.0 Hz),1.45-1.52 (9H, m), 2.84-2.94 (2H, m), 3.55-3.70 (1H, m), 4.00-4.22 (3H,m), 4.33 (2H, q, J=6.9 Hz), 5.33-5.53 (1H, m), 6.58 (1H, d, J=8.7 Hz),7.64-7.73 (1H, m).

(Step 2)

2N Aqueous lithium hydroxide solution (38.0 mL, 76.03 mmol) was added toa solution of 5-ethyl 6-tert-butyl2-ethoxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (4.44 g,12.67 mmol) in a mixed solvent of EtOH (20 mL) and THF (20 mL), and themixture was stirred at room temperature for 1.5 hr. To the reactionmixture was added ice water, and 2N hydrochloric acid was added theretountil the pH of the mixture became 4. Then, the mixture was extractedthree times with a mixed solvent of ethyl acetate/THF (3:1). The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure to give6-(tert-butoxycarbonyl)-2-ethoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylicacid (4.03 g, 12.50 mmol, 99%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.37 (3H, t, J=7.2 Hz), 1.42-1.53 (9H, m),2.89 (2H, brs), 3.63 (1H, dt, J=13.3, 6.8 Hz), 3.95-4.08 (1H, m), 4.32(2H, q, J=6.9 Hz), 5.35-5.57 (1H, m), 6.59 (1H, d, J=8.3 Hz), 7.68 (1H,d, J=8.7 Hz).

(Step 3)

T3P (3.84 mL, 6.45 mmol) was added to a solution of6-(tert-butoxycarbonyl)-2-ethoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylicacid (1.386 g, 4.3 mmol), 3,5-difluoro-4-(trimethylsilyl)aniline (0.866g, 4.30 mmol), DIEA (3.74 mL, 21.50 mmol) and DMAP (0.578 g, 4.73 mmol)in ethyl acetate (31 mL) at room temperature, and the mixture wasstirred at 65° C. for 15 hr. To the reaction mixture was added water,and the mixture was extracted three times with ethyl acetate. Theorganic layer was washed with 10% aqueous citric acid solution, aqueoussodium hydrogen carbonate solution and brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theprecipitate was washed with cooled hexane to give tert-butyl5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-ethoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.82 g, 3.60 mmol, 84%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.32 (9H, t, J=1.3 Hz), 1.38 (3H, t, J=7.2Hz), 1.53 (9H, s), 2.81-3.01 (2H, m), 3.46 (1H, brs), 3.99-4.09 (1H, m),4.29-4.38 (2H, m), 5.57 (1H, brs), 6.62 (1H, d, J=8.7 Hz), 6.98-7.06(2H, m), 7.46 (1H, brs), 9.07 (1H, brs).

(Step 4)

tert-Butyl5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-ethoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.80 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-ethoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(760 mg, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-ethoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(780 mg, >99% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALPAK AD (NF001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 5)

Cooled TFA (10.5 mL) was added to tert-butyl(R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-ethoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(757 mg, 1.50 mmol), and the mixture was stirred at room temperature for3 min. The reaction mixture was added to ice and aqueous sodium hydrogencarbonate solution, and 8N aqueous sodium hydroxide solution andpotassium carbonate were added thereto until the pH of the mixturebecame 8. Then, the mixture was extracted three times with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reduced pressureto give(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-ethoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(589 mg, 1.452 mmol, 97-) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.32 (9H, s), 1.37 (3H, t, J=7.0 Hz), 1.73(1H, brs), 2.72-2.96 (2H, m), 3.10-3.29 (2H, m), 4.31 (2H, q, J=7.2 Hz),4.57 (1H, s), 6.59 (1H, d, J=8.7 Hz), 7.05-7.13 (2H, m), 7.80 (1H, d,J=8.7 Hz), 9.59 (1H, s).

(Step 6)

HATU (126 mg, 0.33 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-ethoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(103 mg, 0.25 mmol), 3-hydroxyisoxazole-5-carboxylic acid (39.3 mg, 0.30mmol) and DIEA (88 μL, 0.51 mmol) in DMF (1.3 mL) at room temperature,and the mixture was stirred at room temperature for 15 hr. To thereaction mixture was added water, and the mixture was extracted threetimes with ethyl acetate. The organic layer was washed with brine, anddried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 15→85% ethyl acetate/hexane) togive the title compound (94.2 mg, 0.182 mmol, 71.8-) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.33 (9H, s), 1.39 (3H, t, J=7.0 Hz), 2.83(1H, s), 2.98-3.09 (1H, m), 3.14-3.28 (1H, m), 3.75-3.88 (1H, m),4.30-4.41 (3H, m), 5.94 (1H, s), 6.60 (1H, s), 6.66 (1H, d, J=8.7 Hz),7.06 (2H, d, J=8.7 Hz), 7.39 (1H, d, J=8.3 Hz), 9.13 (1H, s).

Example 127(5S)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-ethoxy-6-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide

The title compound was synthesized using tert-butyl(S)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-ethoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate,by the reaction and purification in the same manner as in Steps 5 to 6of Example 126.

¹H NMR (300 MHz, CDCl₃): δ 0.33 (9H, s), 1.39 (3H, t, J=7.0 Hz), 2.83(1H, s), 2.97-3.09 (1H, m), 3.13-3.28 (1H, m), 3.76-3.89 (1H, m),4.30-4.40 (3H, m), 5.94 (1H, s), 6.60 (1H, s), 6.66 (1H, d, J=8.3 Hz),7.01-7.09 (2H, m), 7.40 (1H, d, J=8.7 Hz), 9.16 (1H, s).

Example 128(5R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-ethoxy-6-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide

HATU (127 mg, 0.33 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-ethoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(104 mg, 0.26 mmol), 2-(3-hydroxyisoxazol-5-yl)acetic acid (44.0 mg,0.31 mmol) and DIEA (89 μL, 0.51 mmol) in DMF (1.3 mL) at roomtemperature, and the mixture was stirred for 15 hr. To the reactionmixture was added water, and the mixture was extracted three times withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 15→80% MeOH/ethyl acetate), andcrystallized from IPE/hexane to give the title compound (58.2 mg, 0.110mmol, 42.8%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.30 (9H, s), 1.35 (3H, t, J=7.0 Hz),2.88-3.00 (2H, m), 3.14 (1H, dt), 3.88-4.02 (4H, m), 4.30 (2H, qd,J=7.0, 2.1 Hz), 5.94 (1H, s), 5.97 (1H, s), 6.63 (1H, d, J=8.7 Hz), 6.90(2H, d, J=8.7 Hz), 7.43 (1H, d, J=8.7 Hz), 9.27 (1H, s).

Example 1295-((5R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-ethoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-oxopentanoicacid

Dihydro-2H-pyran-2,6(3H)-dione (39.0 mg, 0.34 mmol) was added to asolution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-ethoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(132 mg, 0.33 mmol) and TEA (50 μL, 0.36 mmol) in THF (2.8 mL) at roomtemperature, and the mixture was stirred at room temperature for 15 hr.To the reaction mixture was added water, and 2N hydrochloric acid wasadded thereto until the pH of the mixture became 4. Then, the mixturewas extracted three times with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (Diol, solvent gradient; 20→100% ethylacetate/hexane) to give the title compound (63.3 mg, 0.122 mmol, 37.4%))as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.27 (9H, s), 1.37 (3H, t, J=7.0 Hz),2.08-2.19 (2H, m), 2.43 (2H, t), 2.55 (1H, ddd, J=14.6, 9.0, 5.5 Hz),2.91-3.08 (2H, m), 3.20-3.31 (1H, m), 3.89-3.99 (1H, m), 4.06-4.17 (1H,m), 4.33 (2H, q, J=7.2 Hz), 5.83 (1H, s), 6.60 (1H, d, J=8.7 Hz),6.74-6.82 (2H, m), 7.72 (1H, d, J=8.7 Hz), 9.92 (1H, s).

Example 1305-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

Dihydro-2H-pyran-2,6(3H)-dione (58.9 mg, 0.52 mmol) was added to asolution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(209 mg, 0.52 mmol) and TEA (0.073 mL, 0.52 mmol) in THF (2 mL) at roomtemperature, and the mixture was stirred at 60° C. for 4 hr. Thereaction mixture was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(solvent gradient; 10→100% ethyl acetate/hexane) to give the titlecompound (170 mg, 0.328 mmol, 63.4%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 0.30 (9H, s), 1.75 (2H, quin, J=7.3 Hz),2.18-2.33 (2H, m), 2.37-2.62 (2H, m), 2.78-2.92 (1H, m), 3.04-3.20 (1H,m), 3.27 (3H, s), 3.47-3.64 (1H, m), 3.96-4.12 (1H, m), 4.36 (2H, s),5.69 (1H, s), 7.10-7.31 (4H, m), 7.51 (1H, d, J=7.6 Hz), 10.82 (1H, s),12.04 (1H, brs).

[α]_(D) ²⁵ −3.8 (c 0.2275, MeOH)

Example 131(1R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

A solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(67 mg, 0.15 mmol), DIEA (0.032 mL, 0.18 mmol),3-hydroxyisoxazole-5-carboxylic acid (23.53 mg, 0.18 mmol) and COMU(71.6 mg, 0.17 mmol) in DMF (2 mL) was stirred at 0° C. for 2 hr. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified twice by silica gel columnchromatography (Diol, solvent gradient; 5→90% ethyl acetate/hexane) togive the title compound (36.0 mg, 0.070 mmol, 46.0%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.30 (9H, s), 2.92 (1H, dt, J=16.0, 4.3 Hz),3.08-3.23 (1H, m), 3.28 (3H, s), 3.68-3.89 (1H, m), 4.10-4.26 (1H, m),4.38 (2H, s), 5.73 (1H, s), 6.60 (1H, s), 7.08-7.32 (4H, m), 7.58 (1H,d, J=8.3 Hz), 10.99 (1H, s), 11.77 (1H, s).

Example 132(1R)—N-(4-tert-butyl-3-fluorophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

T3P (2.75 mL, 4.67 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (500 mg, 1.56 mmol), 4-(tert-butyl)-3-fluoroaniline (260 mg, 1.56mmol), DIEA (1.359 mL, 7.78 mmol) and DMAP (190 mg, 1.56 mmol) in ethylacetate (5 mL), and the mixture was stirred at 60° C. for 2 hr. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 32→40% ethyl acetate/hexane) to givetert-butyl1-((4-(tert-butyl)-3-fluorophenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(500 mg, 1.063 mmol, 68.3%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.33 (9H, s), 1.52 (9H, s), 2.83-2.99 (1H,m), 3.39 (3H, s), 3.48-3.84 (2H, m), 4.44 (2H, s), 5.64 (1H, brs), 7.04(1H, d, J=8.3 Hz), 7.13-7.26 (4H, m), 7.33-7.43 (1H, m), 8.83 (1H, s).

(Step 2)

tert-Butyl1-((4-(tert-butyl)-3-fluorophenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.83 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((4-(tert-butyl)-3-fluorophenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.83 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-1-((4-(tert-butyl)-3-fluorophenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.83 g, >99% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALPAK IA (QK001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

4N Hydrogen chloride/ethyl acetate (2 mL) was added to a solution oftert-butyl(R)-1-((4-(tert-butyl)-3-fluorophenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.24 g, 0.51 mmol) in ethyl acetate (2 mL) at room temperature, and themixture was stirred overnight at room temperature. The reaction mixturewas concentrated under reduced pressure, and the precipitate wascollected by filtration ethyl acetate/hexane to give(R)—N-(4-(tert-butyl)-3-fluorophenyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (0.208 g, 0.511 mmol, 100%) as a white solid.

MS(API): Calculated 406.92. Found 369.2 (M−HCl−H).

(Step 4)

HATU (233 mg, 0.61 mmol) was added to a solution of(R)—N-(4-(tert-butyl)-3-fluorophenyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (208 mg, 0.51 mmol), 2-(3-hydroxyisoxazol-5-yl)acetic acid(88 mg, 0.61 mmol) and DIEA (0.214 mL, 1.23 mmol) in DMF (3 mL) at roomtemperature, and the mixture was stirred at room temperature for 2 hr.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 5→90% ethyl acetate/hexane) togive the title compound (157 mg, 0.317 mmol, 62.0%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 1.29 (9H, s), 2.78-2.93 (1H, m), 3.06-3.20(1H, m), 3.27 (3H, s), 3.58-3.74 (1H, m), 3.87-4.16 (3H, m), 4.36 (2H,s), 5.74 (1H, s), 5.91 (1H, s), 7.15-7.31 (4H, m), 7.40-7.50 (1H, m),7.55 (1H, d, J=7.6 Hz), 10.60 (1H, s), 11.10 (1H, s).

Example 133(1R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

T3P (8.24 mL, 14.00 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (1.5 g, 4.67 mmol),7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine (0.837 g, 4.67 mmol),DIEA (4.08 mL, 23.34 mmol) and DMAP (0.570 g, 4.67 mmol) in ethylacetate (5 mL), and the mixture was stirred at 60° C. for 2 hr. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 32→40% ethyl acetate/hexane) to givetert-butyl1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.600 g, 3.32 mmol, 71.0%) as a white solid.

MS(API): Calculated 482.6. Found 481.3 (M−H).

(Step 2)

tert-Butyl1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.60 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.77 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.73 g, >99% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALCEL OD (NL001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

4N Hydrogen chloride/ethyl acetate (4 mL) was added to a solution oftert-butyl(R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.77 g, 1.60 mmol) in ethyl acetate (2 mL), and the mixture was stirredovernight at room temperature. The precipitate was collected byfiltration ethyl acetate/hexane to give(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (0.730 g, 1.743 mmol, 109%) as a white solid.

MS(API): Calculated 418.9. Found 381.2 (M−HCl−H).

(Step 4)

A solution of(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (250 mg, 0.60 mmol), DIEA (0.250 mL, 1.43 mmol),3-hydroxyisoxazole-5-carboxylic acid (92 mg, 0.72 mmol) and COMU (281mg, 0.66 mmol) in DMF (2 mL) was stirred at 0° C. for 2 hr. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 20→100% ethyl acetate/hexane,0→10% MeOH/ethyl acetate), and crystallized from ethyl acetate/hexane togive the title compound (204 mg, 0.413 mmol, 69.3%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 1.28 (6H, s), 1.87 (2H, t, J=7.4 Hz),2.79-2.99 (3H, m), 3.07-3.21 (1H, m), 3.28 (3H, s), 3.79 (1H, ddd,J=12.4, 8.2, 4.0 Hz), 4.10-4.24 (1H, m), 4.38 (2H, s), 5.49-5.84 (1H,m), 6.29-6.68 (1H, m), 7.07-7.30 (4H, m), 7.49-7.64 (1H, m), 10.25-10.75(1H, m), 11.78 (1H, brs).

[α]_(D) ²⁵ +0.9 (c 0.2525, MeOH)

Example 1345-((1R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

The title compound was synthesized using(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride, by the reaction and purification in the same manner as inExample 109.

¹H NMR (300 MHz, DMSO-d₆): δ 1.28 (6H, s), 1.74 (2H, dq, J=14.9, 7.4Hz), 1.86 (2H, t, J=7.4 Hz), 2.17-2.33 (4H, m), 2.77-2.91 (3H, m),3.06-3.19 (1H, m), 3.27 (3H, s), 3.48-3.67 (1H, m), 3.91-4.13 (1H, m),4.36 (2H, s), 5.54-5.80 (1H, m), 7.07-7.29 (4H, m), 7.52 (1H, d, J=7.9Hz), 10.33-10.55 (1H, m), 11.96 (1H, brs).

Example 1355-((1R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid (Step 1)

tert-Butyl1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.10 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.53 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.51 g, 96.7% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALCEL OD (NL001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 2)

Cooled TFA (5.0 mL) was added to tert-butyl(R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(526 mg, 1.11 mmol), and the mixture was stirred at room temperature for2 min. The reaction mixture was added to ice and aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by NH-silica gel column chromatography(solvent gradient; 20→50% ethyl acetate/hexane) to give(R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(350.3 mg, 0.940 mmol, 84%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.28 (9H, d, J=0.8 Hz), 2.68-2.82 (1H, m),2.83-2.97 (1H, m), 3.10-3.19 (2H, m), 3.79 (3H, s), 4.64 (1H, s), 6.65(1H, d, J=2.6 Hz), 6.79 (1H, dd, J=8.5, 2.6 Hz), 7.18 (1H, dd, J=7.9,1.9 Hz), 7.27 (1H, s), 7.46 (1H, dd, J=10.6, 1.9 Hz), 7.53 (1H, d, J=8.6Hz), 9.46 (1H, s)

(Step 3)

Dihydro-2H-pyran-2,6(3H)-dione (36.8 mg, 0.32 mmol) was added to asolution of(R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(80 mg, 0.21 mmol) and TEA (0.060 mL, 0.43 mmol) in THF (2.0 mL) at roomtemperature, and the mixture was stirred at room temperature for 3 hr.The reaction mixture was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent gradient; 50→100% ethyl acetate/hexane) to give the titlecompound (27.9 mg, 0.057 mmol, 26.7%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 0.25 (9H, s), 1.65-1.85 (2H, m), 2.22-2.32(2H, m), 2.36-2.60 (2H, m), 2.72-2.88 (1H, m), 3.05-3.19 (1H, m),3.46-3.58 (1H, m), 3.72 (3H, s), 3.95-4.08 (1H, m), 5.57-5.71 (1H, m),6.76-6.87 (2H, m), 7.25-7.38 (2H, m), 7.41-7.52 (2H, m), 10.53-10.66(1H, m), 11.95 (1H, brs).

[α]_(D) ²⁵ −7.7 (c 0.2525, MeOH)

Example 136(5R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-2-(methoxymethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(Step 1)

Trifluoromethanesulfonic anhydride (16.35 mL, 96.79 mmol) was added to asolution of 5-ethyl 6-tert-butyl2-hydroxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (15.6 g,48.39 mmol) in pyridine (150 mL) at 0° C., and the mixture was stirredat room temperature for 1 hr. The reaction mixture was concentratedunder reduced pressure, and to the obtained residue were added water andethyl acetate. The organic layer was washed with 10% aqueous citric acidsolution, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent; ethyl acetate/hexane) to give5-ethyl 6-tert-butyl2-(((trifluoromethyl)sulfonyl)oxy)-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate(18.0 g, 39.6 mmol, 82%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.23-1.33 (3H, m), 1.49 (9H, d, J=8.3 Hz),2.89-3.11 (2H, m), 3.42-3.65 (1H, m), 4.14-4.36 (3H, m), 5.46-5.74 (1H,m), 7.05 (1H, d, J=8.3 Hz), 8.06 (1H, d, J=8.3 Hz).

(Step 2)

A solution of 5-ethyl 6-tert-butyl2-(((trifluoromethyl)sulfonyl)oxy)-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate(18.0 g, 39.61 mmol), Pd(PPh₃)₄ (2.289 g, 1.98 mmol) and zinc cyanide(5.12 g, 43.57 mmol) in DMF (270 mL) was stirred at 100° C. for 5 hr. Tothe reaction mixture was added ethyl acetate, and the insolublesubstance was removed by filtration. The filtrate was washed with waterand brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent; ethyl acetate/hexane) to give5-ethyl 6-tert-butyl2-cyano-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (12.4 g,37.4 mmol, 94%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.24-1.33 (3H, m), 1.50 (9H, d, J=8.7 Hz),3.01-3.16 (2H, m), 3.48-3.69 (1H, m), 4.14-4.32 (3H, m), 5.51-5.77 (1H,m), 7.58 (1H, d, J=7.9 Hz), 8.01 (1H, d, J=7.9 Hz).

(Step 3)

2N Aqueous sodium hydroxide solution (56.1 mL, 112.26 mmol) was added toa solution of 5-ethyl 6-tert-butyl2-cyano-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (12.4 g,37.42 mmol) in a mixed solvent of EtOH (100 mL) and THF (100 mL) at roomtemperature, and the mixture was stirred at room temperature for 5 hr.2N Hydrochloric acid was added thereto until the pH of the reactionmixture became 4, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure to give crude6-(tert-butoxycarbonyl)-2-(ethoxycarbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylicacid (11.8 g, 33.7 mmol, 90%) as a white solid.

(Step 4)

T3P (25.4 mL, 43.22 mmol) was added to a solution of the crude6-(tert-butoxycarbonyl)-2-(ethoxycarbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylicacid (5.55 g, 15.85 mmol), 3,5-difluoro-4-(trimethylsilyl)aniline (2.9g, 14.41 mmol), DMAP (1.936 g, 15.85 mmol) and DIEA (12.58 mL, 72.04mmol) in ethyl acetate (100 mL) at room temperature, and the mixture wasstirred at 80° C. for 2 hr. To the reaction mixture was added water, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent; ethyl acetate/hexane) to give2-ethyl 6-tert-butyl5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-7,8-dihydro-,6-naphthyridine-2,6(5H)-dicarboxylate (3.44 g, 6.45 mmol, 44.7%) as awhite solid.

MS(API): Calculated 533.6. Found 532.3 (M−H).

(Step 5)

Sodium borohydride (0.723 g, 19.11 mmol) was added to a mixture of2-ethyl 6-tert-butyl5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-7,8-dihydro-1,6-naphthyridine-2,6(5H)-dicarboxylate(3.4 g, 6.37 mmol) and calcium chloride (1.061 g, 9.56 mmol) in a mixedsolvent of EtOH (35 mL) and THF (35 mL) at 0° C., and the mixture wasstirred at room temperature for 5 hr. The reaction mixture wasneutralized with IN hydrochloric acid, and the mixture was extractedwith ethyl acetate. The organic layer was washed with water and brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent; ethyl acetate/hexane) to give tert-butyl5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-(hydroxymethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(2.09 g, 4.25 mmol, 66.7%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 0.33 (9H, t, J=1.3 Hz), 1.55 (9H, s),2.98-3.11 (2H, m), 3.51 (1H, brs), 3.72 (1H, t, J=4.9 Hz), 4.02-4.12(1H, m), 4.75 (2H, d, J=4.5 Hz), 5.69 (1H, brs), 6.95-7.07 (2H, m), 7.16(1H, d, J=7.9 Hz), 7.61 (1H, brs), 9.12 (1H, brs).

(Step 6)

Methanesulfonyl chloride (0.655 mL, 8.46 mmol) was added to a solutionof tert-butyl5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-(hydroxymethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(2.08 g, 4.23 mmol) and TEA (1.179 mL, 8.46 mmol) in THF (40 mL) at 0°C., and the mixture was stirred at the same temperature for 1 hr. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent; ethyl acetate/hexane) to give tert-butyl5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-(((methylsulfonyl)oxy)methyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.97 g, 3.46 mmol, 82%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 0.33 (9H, t, J=1.3 Hz), 1.55 (9H, s),2.97-3.08 (2H, m), 3.09 (3H, s), 3.50 (1H, brs), 4.06-4.16 (1H, m), 5.31(2H, s), 5.72 (1H, brs), 6.95-7.06 (2H, m), 7.39 (1H, d, J=8.3 Hz), 7.66(1H, brs), 9.11 (1H, brs).

(Step 7)

A solution of tert-butyl5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-(((methylsulfonyl)oxy)methyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.80 g, 3.16 mmol) in MeOH (40 mL) was stirred overnight at 60° C. Thereaction mixture was neutralized with aqueous sodium hydrogen carbonatesolution, and the mixture was extracted twice with ethyl acetate. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 5→100% ethyl acetate/hexane; 0→10. MeOH/ethyl acetate) to givetert-butyl5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-(methoxymethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(760 mg, 1.503 mmol) andN-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(methoxymethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(350 mg, 0.863 mmol), each as a white solid.

NMR spectrum of tert-butyl5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-(methoxymethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

¹H NMR (300 MHz, CDCl₃): δ 0.33 (9H, s), 1.54 (9H, s), 3.04 (2H, brs),3.47 (5H, s), 4.56 (2H, s), 5.57-5.76 (1H, m), 7.02 (2H, d, J=8.7 Hz),7.34 (1H, d, J=7.9 Hz), 7.48-7.74 (1H, m), 8.83-9.30 (1H, m).

NMR spectrum ofN-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(methoxymethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide

¹H NMR (300 MHz, CDCl₃): δ 0.26-0.40 (9H, m), 2.85-3.11 (2H, m),3.12-3.36 (2H, m), 3.46 (3H, s), 4.53 (2H, d, J=1.9 Hz), 4.66 (1H, s),7.09 (2H, d, J=9.1 Hz), 7.29 (1H, d, J=8.3 Hz), 7.96 (1H, d, J=7.9 Hz),9.55-9.67 (1H, m).

(Step 8)

Boc₂O (0.240 mL, 1.04 mmol) was added to a solution ofN-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(methoxymethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(350 mg, 0.86 mmol) and TEA (0.144 mL, 1.04 mmol) in THF (7.0 mL) atroom temperature, and the mixture was stirred at room temperature for 3hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent; ethyl acetate/hexane) to give tert-butyl5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-(methoxymethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(429.8 mg, 0.850 mmol, 98%) as a white solid.

MS(API): Calculated 505.6. Found 504.2 (M−H).

(Step 9)

tert-Butyl5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-(methoxymethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.53 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-(methoxymethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(0.54 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-(methoxymethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(0.50 g, >99% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALCEL OD (NL001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 10)

Cooled TFA (3.0 mL) was added to tert-butyl(R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-(methoxymethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(540 mg, 1.07 mmol) at room temperature, and the mixture was stirred atroom temperature for 5 min. The reaction mixture was added to ice andaqueous sodium hydrogen carbonate solution, and the mixture wasextracted with ethyl acetate. The organic layer was dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure to give(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(methoxymethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(415.3 mg, 1.024 mmol, 96%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.29-0.37 (9H, m), 2.86-3.13 (2H, m),3.14-3.35 (2H, m), 3.41-3.50 (3H, m), 4.46-4.60 (2H, m), 4.66 (1H, s),5.05 (1H, brs), 7.03-7.16 (2H, m), 7.29 (1H, d, J=8.3 Hz), 7.96 (1H, d,J=7.9 Hz), 9.62 (1H, s).

(Step 11)

HATU (56.3 mg, 0.15 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(methoxymethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(50 mg, 0.12 mmol), 3-hydroxyisoxazole-5-carboxylic acid (19.10 mg, 0.15mmol) and DIEA (0.042 mL, 0.25 mmol) in DMF (2.0 mL) at roomtemperature, and the mixture was stirred at room temperature for 2 hr.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→50% ethyl acetate/hexane) to givethe title compound (35.3 mg, 0.068 mmol, 55.4%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 0.31 (9H, s), 2.96-3.11 (1H, m), 3.13-3.26(1H, m), 3.35 (3H, s), 3.92-4.08 (1H, m), 4.12-4.29 (1H, m), 4.47 (2H,s), 5.72-5.86 (1H, m), 6.40-6.68 (1H, m), 7.23 (2H, d, J=9.4 Hz), 7.36(1H, d, J=7.9 Hz), 7.96 (1H, d, J=7.9 Hz), 10.68-11.10 (1H, m), 11.79(1H, brs).

Example 137(1R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-2-((3-hydroxy-,2-oxazol-5-yl)carbonyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

T3P (3.24 mL, 5.51 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (0.59 g, 1.84 mmol), 3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)aniline (0.395 g, 1.84 mmol), DIEA (1.603 mL, 9.18 mmol) and DMAP (0.224g, 1.84 mmol) in ethyl acetate (5 mL), and the mixture was stirred at60° C. for 2 days. To the reaction mixture was added water, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 5→60% ethylacetate/hexane) to give tert-butyl1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.690 g, 1.331 mmol, 72.5%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.42 (6H, t, J=2.3 Hz), 1.52 (9H, s), 2.90(2H, t, J=6.4 Hz), 3.30 (3H, s), 3.39 (3H, s), 3.51 (2H, s), 3.55-3.82(2H, m), 4.44 (2H, s), 5.61 (1H, brs), 6.95-7.11 (2H, m), 7.15-7.24 (3H,m), 8.94 (1H, brs).

(Step 2)

tert-Butyl1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.76 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.35 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.36 g, >99% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALCEL OD (NL001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

4N Hydrogen chloride/ethyl acetate (4 mL) was added to tert-butyl(R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(350 mg, 0.67 mmol) at room temperature, and the mixture was stirredovernight at room temperature. The reaction mixture was concentratedunder reduced pressure to give(R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (307 mg, 0.675 mmol, 100%) as a white solid.

MS(API): Calculated 454.9. Found 417.2 (M−HCl−H).

(Step 4)

A solution of(R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (307 mg, 0.73 mmol), DIEA (0.308 mL, 1.76 mmol),3-hydroxyisoxazole-5-carboxylic acid (114 mg, 0.88 mmol) and COMU (346mg, 0.81 mmol) in DMF (4 mL) was stirred at 0° C. for 2 hr. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 20→100% ethyl acetate/hexane),and then silica gel column chromatography (solvent gradient; 20→100%ethyl acetate/hexane), and crystallized from ethyl acetate/hexane togive the title compound (164 mg, 0.310 mmol, 42.2%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 1.36 (6H, s), 2.84-2.99 (1H, m), 3.07-3.22(4H, m), 3.28 (3H, s), 3.44 (2H, s), 3.66-3.83 (1H, m), 4.08-4.24 (1H,m), 4.38 (2H, s), 5.52-5.81 (1H, m), 6.41-6.68 (1H, m), 7.19 (4H, d,J=13.2 Hz), 7.57 (1H, d, J=8.3 Hz), 10.88 (1H, s), 11.76 (1H, s).

[α]_(D) ²⁵ −7.9 (c 0.2505, MeOH)

Example 138(5R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-2-(methoxymethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide

HATU (56.3 mg, 0.15 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(methoxymethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(50 mg, 0.12 mmol), 2-(3-hydroxyisoxazol-5-yl)acetic acid and DIEA(0.042 mL, 0.25 mmol) in DMF (2.0 mL) at room temperature, and themixture was stirred at room temperature for 2 hr. To the reactionmixture was added aqueous sodium hydrogen carbonate solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 0→50% ethylacetate/hexane), and recrystallized from ethyl acetate/hexane to givethe title compound (20.0 mg, 0.038 mmol, 30.6%) as white crystals.

¹H NMR (300 MHz, DMSO-dr): δ 0.30 (9H, s), 2.89-3.05 (1H, m), 3.08-3.22(1H, m), 3.34 (3H, s), 3.79-3.96 (1H, m), 3.96-4.19 (3H, m), 4.38-4.53(2H, m), 5.75-5.97 (2H, m), 7.21 (2H, d, J=9.4 Hz), 7.33 (1H, d, J=7.9Hz), 7.83-7.96 (1H, m), 10.76-10.99 (1H, m), 11.13 (1H, brs).

Example 1395-((5R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-(methoxymethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-oxopentanoicacid

The title compound was synthesized using(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(methoxymethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide,by the reaction and purification in the same manner as in Example 109.

¹H NMR (300 MHz, DMSO-d₆): δ 0.30 (9H, s), 1.63-1.84 (2H, m), 2.15-2.40(2H, m), 2.54-2.66 (1H, m), 2.87-3.04 (1H, m), 3.06-3.23 (1H, m), 3.34(3H, s), 3.59 (1H, s), 3.71-3.90 (1H, m), 3.98-4.14 (1H, m), 4.45 (2H,s), 5.79 (1H, s), 7.15-7.36 (3H, m), 7.90 (1H, d, J=7.9 Hz), 10.78-10.95(1H, m), 12.06 (1H, brs).

Example 1405-((5R)-5-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-oxopentanoicacid (Step 1)

T3P (8.45 mL, 14.21 mmol) was added to a solution of6-(tert-butoxycarbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylicacid (2.92 g, 9.47 mmol), 3-fluoro-4-(trimethylsilyl)aniline (1.736 g,9.47 mmol), DIEA (8.25 mL, 47.35 mmol) and DMAP (1.273 g, 10.42 mmol) inethyl acetate (70 mL), and the mixture was stirred at 65° C. for 15 hr.To the reaction mixture was added water, and the mixture was extractedthree times with ethyl acetate. The organic layer was washed with 10%aqueous citric acid solution, aqueous sodium hydrogen carbonate solutionand brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure to give tert-butyl5-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(3.66 g, 7.73 mmol, 82%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.28 (9H, s), 1.53 (9H, s), 2.84-3.03 (2H,m), 3.46 (1H, brs), 3.92 (3H, s), 4.01-4.12 (1H, m), 5.59 (1H, brs),6.64 (1H, d, J=8.3 Hz), 7.11 (1H, dd, J=8.1, 1.3 Hz), 7.29 (1H, dd,J=7.9, 6.4 Hz), 7.39 (1H, dd, J=10.6, 1.9 Hz), 7.47 (1H, brs), 8.94 (1H,brs).

(Step 2)

tert-Butyl5-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.30 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-5-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(0.62 g, >99 ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-5-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(0.61 g, % ee was not measured), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALCEL OD (NL001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

Cooled TFA (8.5 mL) was added to tert-butyl(R)-5-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(622 mg, 1.31 mmol) at room temperature, and the mixture was stirred atroom temperature for 3 min. The reaction mixture was added to ice andaqueous sodium hydrogen carbonate solution, and aqueous sodium hydrogencarbonate solution was added thereto until the pH of the mixture became8. Then, the mixture was extracted three times with ethyl acetate. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure to give(R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(472 mg, 1.264 mmol, 96-) as a white solid.

MS(API): Calculated 373.5. Found 374.3 (M+H).

(Step 4)

Dihydro-2H-pyran-2,6(3H)-dione (159 mg, 1.39 mmol) was added to asolution of(R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-methoxy-5,6,7,8-tetrahydro-,6-naphthyridine-5-carboxamide (472 mg, 1.26 mmol) and TEA (211 μL, 1.51mmol) in THF (12 mL) at room temperature, and the mixture was stirred atroom temperature for 15 hr. To the reaction mixture was added water, and2N hydrochloric acid was added thereto until the pH of the mixturebecame 4. Then, the mixture was extracted three times with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 20→100% ethyl acetate/hexane) togive the title compound (411.3 mg, 0.844 mmol, 66.7-) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.23 (9H, s), 1.99-2.20 (2H, m), 2.41-2.62(3H, m), 2.89 (1H, dt, J=14.8, 5.8 Hz), 2.98-3.10 (1H, m), 3.17-3.27(1H, m), 3.92 (3H, s), 3.94-4.08 (2H, m), 5.93 (1H, s), 6.63 (1H, d,J=8.3 Hz), 6.91 (1H, dd, J=8.1, 1.7 Hz), 7.08-7.19 (2H, m), 7.69 (1H, d,J=8.7 Hz), 9.73 (1H, s).

[α]_(D) ²⁵ +97.8 (c 0.2525, MeOH)

Example 1415-((1R)-1-((3,5-difluoro-4-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

The title compound was synthesized using(R)—N-(3,5-difluoro-4-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide,by the reaction and purification in the same manner as in Example 109.

¹H NMR (300 MHz, DMSO-d₆): δ 1.30 (3H, t, J=7.0 Hz), 1.35 (6H, s),1.62-1.84 (2H, m), 2.19-2.34 (2H, m), 2.38-2.61 (2H, m), 2.68-2.85 (1H,m), 3.04-3.21 (4H, m), 3.33-3.38 (2H, m), 3.40-3.48 (2H, m), 3.49-3.58(3H, m), 3.88-4.08 (3H, m), 5.50-5.66 (1H, m), 6.67-6.89 (2H, m),7.08-7.23 (2H, m), 7.43 (1H, d, J=9.4 Hz), 10.64 (1H, s), 11.98 (1H,brs).

Example 142(1R)—N-(3,5-difluoro-4-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)phenyl)-6-ethoxy-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

The title compound was synthesized using(R)—N-(3,5-difluoro-4-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide,by the reaction and purification in the same manner as in Example 131.

¹H NMR (300 MHz, DMSO-d): δ 1.30 (3H, t, J=7.0 Hz), 1.36 (6H, s),2.78-2.94 (1H, m), 3.07-3.23 (4H, m), 3.34-3.39 (2H, m), 3.42-3.48 (2H,m), 3.54 (2H, s), 3.65-3.81 (1H, m), 4.01 (2H, q, J=6.8 Hz), 4.10-4.22(1H, m), 5.53-5.68 (1H, m), 6.58 (1H, s), 6.72-6.91 (2H, m), 7.09-7.30(2H, m), 7.37-7.60 (1H, m), 10.81 (1H, s), 11.76 (1H, s).

Example 143(1R)—N-(3,5-difluoro-4-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)phenyl)-6-ethoxy-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

Sodium hydride (60% oil, 0.679 g, 16.99 mmol) was added to a solution of2-(4-(bis(4-methoxybenzyl)amino)-2,6-difluorophenyl)-2-methylpropan-1-ol(3.0 g, 6.79 mmol), 1-bromo-2-methoxyethane (1.595 mL, 16.99 mmol) andsodium iodide (7.64 g, 50.96 mmol) in DMF (9 mL) at 5° C., and themixture was stirred at 5° C. for 4 hr. DMF (3 mL) was added againthereto, and the mixture was stirred at room temperature for 14 hr. Tothe reaction mixture was added aqueous ammonium chloride solution, andthe mixture was extracted twice with ethyl acetate. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 5→20% ethylacetate/hexane) to give3,5-difluoro-N,N-bis(4-methoxybenzyl)-4-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)aniline(2.65 g, 5.30 mmol, 78%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.40 (6H, t, J=2.3 Hz), 3.33 (3H, s),3.47-3.52 (2H, m), 3.53-3.58 (2H, m), 3.59 (2H, s), 3.79 (6H, s), 4.46(4H, s), 6.17 (2H, d, J=14.4 Hz), 6.82-6.90 (4H, m), 7.10 (4H, d, J=8.7Hz).

(Step 2)

A solution of3,5-difluoro-N,N-bis(4-methoxybenzyl)-4-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)aniline(2.65 g, 5.30 mmol), 1N hydrochloric acid (10.61 mL, 10.61 mmol) and 10%palladium-carbon (0.564 g, 0.27 mmol, 50% wet) in MeOH (100 mL) wasstirred under hydrogen atmosphere (1 atm) at room temperature for 1.5hr. The catalyst was filtered off, and the filtrate was concentratedunder reduced pressure. The obtained residue was dissolved in ethylacetate, the solution was washed with 1N aqueous sodium hydroxidesolution and brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 5→20% ethylacetate/hexane) to give3,5-difluoro-4-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)aniline (1.090g, 4.20 mmol, 79%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.41 (6H, t, J=2.3 Hz), 3.34 (3H, s),3.46-3.52 (2H, m), 3.53-3.58 (2H, m), 3.60 (2H, t, J=1.1 Hz), 3.67-3.86(2H, m), 6.04-6.21 (2H, m).

(Step 3)

T3P (6.81 mL, 11.57 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (1.239 g, 3.86 mmol),3,5-difluoro-4-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)aniline (1 g,3.86 mmol), DIEA (3.37 mL, 19.28 mmol) and DMAP (0.471 g, 3.86 mmol) inethyl acetate (5 mL), and the mixture was stirred at 60° C. for 15 hr.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 5→60% ethyl acetate/hexane) to givetert-butyl1-((3,5-difluoro-4-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.690 g, 3.00 mmol, 78%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.36-1.45 (9H, m), 1.52 (9H, s), 2.72-2.98(2H, m), 3.32 (3H, s), 3.38-3.80 (8H, m), 4.03 (2H, q, J=7.2 Hz), 5.55(1H, brs), 6.71 (1H, d, J=2.3 Hz), 6.79 (1H, dd, J=8.3, 2.6 Hz),6.96-7.09 (2H, m), 7.17 (1H, brs), 8.95 (1H, brs).

(Step 4)

tert-Butyl1-((3,5-difluoro-4-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.70 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((3,5-difluoro-4-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.75 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-1-((3,5-difluoro-4-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.75 g, >99% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALCEL OD (NL001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 5)

Cooled TFA (6 mL) was added to tert-butyl(R)-1-((3,5-difluoro-4-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(H)-carboxylate(0.75 g, 1.33 mmol) at 0° C., and the mixture was stirred at 0° C. for 1hr. The reaction mixture was added to aqueous sodium hydrogen carbonatesolution, and the mixture was extracted with ethyl acetate. The organiclayer was dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure to give(R)—N-(3,5-difluoro-4-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)phenyl)-6-ethoxy-,2,3,4-tetrahydroisoquinoline-1-carboxamide (0.740 g, 1.600 mmol, 120%)as a white solid.

MS(API): Calculated 462.5. Found 461.2 (M−H).

(Step 6)

HATU (46.4 mg, 0.12 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(47 mg, 0.10 mmol), DIEA (0.021 mL, 0.12 mmol) and2-(3-hydroxyisoxazol-5-yl)acetic acid (17.45 mg, 0.12 mmol) in DMF (4mL) at room temperature, and the mixture was stirred at room temperaturefor 1 hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 5→90% ethyl acetate/hexane), andcrystallized from ethyl acetate/hexane to give the title compound (28.0mg, 0.048 mmol, 46.9%) as a white solid.

¹H NMR (300 MHz, DMSO-d): δ 1.30 (3H, t, J=7.0 Hz), 1.35 (6H, s),2.75-2.88 (1H, m), 3.04-3.20 (4H, m), 3.33-3.39 (2H, m), 3.41-3.48 (2H,m), 3.49-3.66 (3H, m), 3.87-4.14 (5H, m), 5.61 (1H, s), 5.90 (1H, s),6.71-6.90 (2H, m), 7.07-7.25 (2H, m), 7.45 (1H, d, J=9.1 Hz), 10.68 (1H,s), 11.11 (1H, brs).

Example 1445-((1R)-1-((4-tert-butyl-3,5-difluorophenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid (Step 1)

T3P (4.34 mL, 7.37 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (790 mg, 2.46 mmol), 4-(tert-butyl)-3,5-difluoroaniline (455 mg,2.46 mmol), DIEA (2.147 mL, 12.29 mmol) and DMAP (300 mg, 2.46 mmol) inethyl acetate (5 mL), and the mixture was stirred at 65° C. for 8 hr. Tothe reaction mixture was added ethyl acetate. The organic layer waswashed with water and brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 5→60%ethyl acetate/hexane) to give tert-butyl1-((4-(tert-butyl)-3,5-difluorophenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(1140 mg, 2.333 mmol, 95%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 1.41 (9H, t, J=2.3 Hz), 1.52 (9H, s),2.80-3.01 (2H, m), 3.39 (3H, s), 3.45-3.83 (2H, m), 4.44 (2H, s), 5.61(1H, brs), 6.93-7.09 (2H, m), 7.14-7.24 (3H, m), 8.96 (1H, s).

(Step 2)

tert-Butyl1-((4-(tert-butyl)-3,5-difluorophenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.05 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((4-(tert-butyl)-3,5-difluorophenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.46 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-1-((4-(tert-butyl)-3,5-difluorophenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.49 g, >99% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALCEL OD (NL001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

4N Hydrogen chloride/ethyl acetate (4 mL) was added to a solution oftert-butyl(R)-1-((4-(tert-butyl)-3,5-difluorophenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.459 g, 0.94 mmol) in ethyl acetate (2 mL) at room temperature, andthe mixture was stirred overnight at room temperature. The reactionmixture was concentrated under reduced pressure, and the residue wascrystallized from ethyl acetate/hexane to give(R)—N-(4-(tert-butyl)-3,5-difluorophenyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (0.403 g, 0.948 mmol, 101%) as white crystals.

MS(API): Calculated 424.9. Found 389.3 (M−HCl+H).

(Step 4)

Dihydro-2H-pyran-2,6(3H)-dione (13.43 mg, 0.12 mmol) was added to asolution of(R)—N-(4-(tert-butyl)-3,5-difluorophenyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (50 mg, 0.12 mmol) and TEA (0.017 mL, 0.12 mmol) in THF (4mL) at room temperature, and the mixture was stirred at 60° C. for 3 hr.The reaction mixture was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(solvent gradient; 5→100% ethyl acetate/hexane, 0→10% MeOH/ethylacetate) to give the title compound (51.0 mg, 0.101 mmol, 86%) as awhite solid.

¹H NMR (300 MHz, DMSO-d): δ 1.38 (9H, t, J=1.9 Hz), 1.73 (2H, dq,J=14.4, 7.4 Hz), 2.26 (4H, dt, J=11.5, 7.3 Hz), 2.78-2.92 (1H, m),3.04-3.19 (1H, m), 3.27 (3H, s), 3.48-3.64 (1H, m), 3.93-4.09 (1H, m),4.36 (2H, s), 5.68 (1H, s), 7.09-7.27 (4H, m), 7.51 (1H, d, J=7.9 Hz),10.70 (1H, s), 12.03 (1H, brs).

[α]_(D) ²⁵ +0.9 (c 0.2505, MeOH)

Example 145(5R)-2-ethoxy-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(Step 1)

T3P (3.60 mL, 6.05 mmol) was added to a solution of6-(tert-butoxycarbonyl)-2-ethoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylicacid (1.30 g, 4.03 mmol),7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine (0.723 g, 4.03 mmol),DIEA (3.51 mL, 20.16 mmol) and DMAP (0.542 g, 4.44 mmol) in ethylacetate (30 mL), and the mixture was stirred at 65° C. for 15 hr. To thereaction mixture was added water, and the mixture was extracted threetimes with ethyl acetate. The organic layer was washed with 10% aqueouscitric acid solution, aqueous sodium hydrogen carbonate solution andbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The precipitate was washed with hexane to givetert-butyl2-ethoxy-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.51 g, 3.12 mmol, 77%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 1.34 (6H, s), 1.38 (3H, t, J=7.0 Hz), 1.53(9H, s), 1.91 (2H, t, J=7.4 Hz), 2.81-3.01 (4H, m), 3.45 (1H, brs),4.01-4.14 (1H, m), 4.28-4.37 (2H, m), 5.56 (1H, brs), 6.61 (1H, d, J=8.3Hz), 7.05-7.12 (2H, m), 7.49 (1H, brs), 8.77 (1H, brs).

(Step 2)

tert-Butyl2-ethoxy-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.50 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-2-ethoxy-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(0.69 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-2-ethoxy-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(0.68 g, >99% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALCEL OD (NL001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

Cooled TFA (9.5 mL) was added to tert-butyl(R)-2-ethoxy-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(688 mg, 1.42 mmol) at room temperature, and the mixture was stirred atroom temperature for 15 min. The reaction mixture was added to ice andaqueous sodium hydrogen carbonate solution, and 8N aqueous sodiumhydroxide solution and potassium carbonate were added thereto until thepH of the mixture became 8. Then, the mixture was extracted three timeswith ethyl acetate. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure to give(R)-2-ethoxy-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(532 mg, 1.387 mmol, 98%) as a white solid.

MS(API): Calculated 383.5. Found 384.3 (M+H).

(Step 4)

HATU (106 mg, 0.28 mmol) was added to a solution of(R)-2-ethoxy-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(82 mg, 0.21 mmol), 3-hydroxyisoxazole-5-carboxylic acid (33.1 mg, 0.26mmol) and DIEA (74 μL, 0.42 mmol) in DMF (1.1 mL) at room temperature,and the mixture was stirred at room temperature for 15 hr. To thereaction mixture was added water, and the mixture was extracted threetimes with ethyl acetate. The organic layer was washed with brine, anddried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 15→85% ethyl acetate/hexane) togive the title compound (66.4 mg, 0.134 mmol, 62.8%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.34 (6H, s), 1.39 (3H, t, J=7.0 Hz), 1.91(2H, t, J=7.4 Hz), 2.82-2.92 (3H, m), 2.97-3.06 (1H, m), 3.13-3.27 (1H,m), 3.76-3.88 (1H, m), 4.30-4.40 (3H, m), 5.94 (1H, s), 6.57 (1H, s),6.65 (1H, d, J=8.7 Hz), 7.08 (1H, s), 7.15 (1H, d, J=11.7 Hz), 7.40 (1H,d, J=8.7 Hz), 8.88 (1H, s).

Example 146(5S)-2-ethoxy-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide

The title compound was synthesized using tert-butyl(S)-2-ethoxy-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate,by the reaction and purification in the same manner as in Steps 3 to 4of Example 145.

¹H NMR (300 MHz, CDCl₃): δ 1.34 (6H, s), 1.39 (3H, t, J=7.0 Hz), 1.91(2H, t, J=7.4 Hz), 2.83-2.92 (3H, m), 2.97-3.07 (1H, m), 3.13-3.26 (1H,m), 3.76-3.88 (1H, m), 4.30-4.39 (3H, m), 5.94 (1H, s), 6.57 (1H, s),6.65 (1H, d, J=8.3 Hz), 7.08 (1H, s), 7.15 (1H, d, J=11.7 Hz), 7.40 (1H,d, J=8.7 Hz), 8.90 (1H, s).

Example 147(5R)-2-ethoxy-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide

HATU (110 mg, 0.29 mmol) was added to a solution of(R)-2-ethoxy-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(85 mg, 0.22 mmol), 2-(3-hydroxyisoxazol-5-yl)acetic acid (38.1 mg, 0.27mmol) and DIEA (77 μL, 0.44 mmol) in DMF (1.1 mL) at room temperature,and the mixture was stirred at room temperature for 15 hr. To thereaction mixture was added water, and the mixture was extracted threetimes with ethyl acetate. The organic layer was washed with brine, anddried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 10→80% ethyl acetate/hexane),and the precipitate was collected by filtration and washed withIPE/hexane to give the title compound (52.4 mg, 0.103 mmol, 46.5%) aswhite crystals.

¹H NMR (300 MHz, CDCl₃): δ 1.30 (6H, s), 1.36 (3H, t, J=7.0 Hz), 1.87(2H, t, J=7.4 Hz), 2.78-3.00 (4H, m), 3.02-3.13 (1H, m), 3.89-3.97 (4H,m), 4.25-4.37 (2H, m), 5.96 (2H, s), 6.62 (1H, d, J=8.7 Hz), 6.94 (1H,s), 7.07 (1H, d, J=11.7 Hz), 7.43 (1H, d, J=8.3 Hz), 8.95 (1H, s).

Example 1485-((5R)-2-ethoxy-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-oxopentanoicacid

The title compound was synthesized using(R)-2-ethoxy-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide,by the reaction and purification in the same manner as in Example 109.

¹H NMR (300 MHz, CDCl₃): δ 1.29 (6H, d, J=1.5 Hz), 1.38 (3H, t, J=7.0Hz), 1.85 (2H, t, J=7.4 Hz), 2.02-2.15 (2H, m), 2.45 (2H, t), 2.57 (1H,dt, J=15.2, 7.3 Hz), 2.71-2.88 (3H, m), 2.94-3.17 (2H, m), 3.91-3.98(2H, m), 4.33 (2H, qd), 5.94 (1H, s), 6.60 (1H, d, J=8.7 Hz), 6.91 (1H,s), 7.04 (1H, d, J=12.1 Hz), 7.59 (1H, d, J=8.7 Hz), 9.37 (1H, s).

Example 149(5R)-2-ethoxy-N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(Step 1)

T3P (3.46 mL, 5.82 mmol) was added to a solution of6-(tert-butoxycarbonyl)-2-ethoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylicacid (1.25 g, 3.88 mmol), 3-fluoro-4-(trimethylsilyl)aniline (0.711 g,3.88 mmol), DIEA (3.38 mL, 19.39 mmol) and DMAP (0.521 g, 4.27 mmol) inethyl acetate (29 mL), and the mixture was stirred at 65° C. for 15 hr.To the reaction mixture was added water, and the mixture was extractedthree times with ethyl acetate. The organic layer was washed with 10%aqueous citric acid solution, aqueous sodium hydrogen carbonate solutionand brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The precipitate was collected byfiltration and washed with cooled hexane to give tert-butyl2-ethoxy-5-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.50 g, 3.08 mmol, 79%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 0.28 (9H, d, J=0.8 Hz), 1.38 (3H, t, J=7.0Hz), 1.53 (9H, s), 2.82-3.01 (2H, m), 3.46 (1H, brs), 4.01-4.14 (1H, m),4.29-4.37 (2H, m), 5.58 (1H, brs), 6.62 (1H, d, J=8.7 Hz), 7.11 (1H, dd,J=7.9, 1.5 Hz), 7.29 (1H, dd), 7.39 (1H, dd, J=10.4, 1.7 Hz), 7.47 (1H,brs), 8.92 (1H, brs).

(Step 2)

tert-Butyl2-ethoxy-5-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.50 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-2-ethoxy-5-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(0.68 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-2-ethoxy-5-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(0.68 g, >99% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALCEL OD (NL001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

Cooled TFA (9.5 mL) was added to tert-butyl(R)-2-ethoxy-5-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(680 mg, 1.39 mmol), and the mixture was stirred at room temperature for3 min. The reaction mixture was added to ice and aqueous sodium hydrogencarbonate solution, and potassium carbonate was added thereto until thepH of the mixture became 8. Then, the mixture was extracted three timeswith ethyl acetate. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was crystallized from cooled hexane to give(R)-2-ethoxy-N-(3-fluoro-4-(trimethylsilyl)phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(525 mg, 1.355 mmol, 97-) as white crystals.

MS(API): Calculated 387.5. Found 388.3 (M+H).

(Step 4)

HATU (98 mg, 0.26 mmol) was added to a solution of(R)-2-ethoxy-N-(3-fluoro-4-(trimethylsilyl)phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(77 mg, 0.20 mmol), 3-hydroxyisoxazole-5-carboxylic acid (30.8 mg, 0.24mmol) and DIEA (69 μL, 0.40 mmol) in DMF (1 mL) at room temperature, andthe mixture was stirred at room temperature for 15 hr. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 15→85% ethyl acetate/hexane) togive the title compound (71.6 mg, 0.144 mmol, 72.3%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.28 (9H, d, J=0.8 Hz), 1.39 (3H, t, J=7.0Hz), 2.83 (1H, s), 2.97-3.07 (1H, m), 3.14-3.28 (1H, m), 3.76-3.87 (1H,m), 4.31-4.40 (3H, m), 5.96 (1H, s), 6.58 (1H, s), 6.66 (1H, d, J=8.7Hz), 7.17 (1H, dd, J=7.9, 1.5 Hz), 7.30 (1H, dd, J=7.7, 6.2 Hz),7.37-7.43 (2H, m), 9.02 (1H, s).

Example 150(5S)-2-ethoxy-N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide

The title compound was synthesized using tert-butyl(S)-2-ethoxy-5-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate,by the reaction and purification in the same manner as in Steps 3 to 4of Example 149.

¹H NMR (300 MHz, CDCl₃): δ 0.28 (9H, s), 1.39 (3H, t, J=7.0 Hz), 2.91(1H, s), 2.98-3.08 (1H, m), 3.14-3.27 (1H, m), 3.77-3.89 (1H, m),4.31-4.40 (3H, m), 5.96 (1H, s), 6.58 (1H, s), 6.66 (1H, d, J=8.7 Hz),7.16 (1H, dd, J=7.9, 1.9 Hz), 7.30 (1H, dd, J=7.9, 6.4 Hz), 7.37-7.44(2H, m), 9.04 (1H, s).

Example 151(5R)-2-ethoxy-N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide

HATU (102 mg, 0.27 mmol) was added to a solution of(R)-2-ethoxy-N-(3-fluoro-4-(trimethylsilyl)phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(80 mg, 0.21 mmol), 2-(3-hydroxyisoxazol-5-yl)acetic acid (35.4 mg, 0.25mmol) and DIEA (72 μL, 0.41 mmol) in DMF (1 mL) at room temperature, andthe mixture was stirred at room temperature for 15 hr. To the reactionmixture was added water, and the mixture was extracted three times withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 10→80% ethyl acetate/hexane),and the obtained precipitate was collected by filtration and washed withIPE/hexane to give the title compound (49.7 mg, 0.097 mmol, 47.0%) as awhite solid.

¹H NMR (300 MHz, CDCl₃): δ 0.25 (9H, s), 1.36 (3H, t, J=7.0 Hz),2.88-3.00 (2H, m), 3.10 (1H, dt), 3.89-3.99 (4H, m), 4.31 (2H, qd,J=7.1, 2.3 Hz), 5.96 (1H, s), 5.98 (1H, s), 6.63 (1H, d, J=8.7 Hz), 7.01(1H, dd, J=7.9, 1.9 Hz), 7.22 (1H, dd, J=7.9, 6.4 Hz), 7.25-7.31 (1H,m), 7.43 (1H, d, J=8.7 Hz), 9.08 (1H, s).

Example 1525-((5R)-2-ethoxy-5-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-oxopentanoicacid

Dihydro-2H-pyran-2,6(3H)-dione (26.6 mg, 0.23 mmol) was added to asolution of(R)-2-ethoxy-N-(3-fluoro-4-(trimethylsilyl)phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(82 mg, 0.21 mmol) and TEA (35 μL, 0.25 mmol) in THF (2 mL) at roomtemperature, and the mixture was stirred at room temperature for 7.5 hr.To the reaction mixture was added water, and 2N hydrochloric acid wasadded thereto until the pH of the mixture became 4. Then, the mixturewas extracted three times with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (Diol, solvent gradient; 20→100% ethylacetate/hexane) to give the title compound (53.1 mg, 0.106 mmol, 50.0%)as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.23 (9H, s), 1.37 (3H, t, J=7.0 Hz),2.04-2.17 (2H, m), 2.44 (2H, t, J=6.2 Hz), 2.50-2.62 (1H, m), 2.88 (1H,dt, J=15.0, 5.9 Hz), 2.96-3.08 (1H, m), 3.19 (1H, dt), 3.93-4.07 (2H,m), 4.29-4.37 (2H, m), 5.92 (1H, s), 6.60 (1H, d, J=8.7 Hz), 6.92 (1H,dd, J=7.9, 1.9 Hz), 7.08-7.19 (2H, m), 7.67 (1H, d, J=8.7 Hz), 9.72 (1H,s).

Example 1535-((1R)-1-((4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid (Step 1)

Sodium hydride (60% oil, 0.408 g, 10.19 mmol) was added to a solution of2-(4-(bis(4-methoxybenzyl)amino)-2,6-difluorophenyl)-2-methylpropan-1-ol(3.0 g, 6.79 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate(1.381 mL, 10.19 mmol) in THF (15 mL) at 5° C., and the mixture wasstirred at 5° C. for 4 hr. To the reaction mixture was added aqueousammonium chloride solution, and the mixture was extracted twice withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 5→20-ethyl acetate/hexane) to give4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluoro-N,N-bis(4-methoxybenzyl)aniline(3.52 g, 6.96 mmol, 102%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.36-1.45 (6H, m), 3.56-3.69 (4H, m),3.78-3.82 (6H, m), 4.47 (4H, s), 5.56-6.03 (1H, m), 6.18 (2H, d, J=14.7Hz), 6.79-6.93 (4H, m), 7.02-7.33 (4H, m).

(Step 2)

A solution of4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluoro-N,N-bis(4-methoxybenzyl)aniline(3.52 g, 6.96 mmol), 10% palladium-carbon (0.741 g, 0.35 mmol, 50% wet)and 1N hydrochloric acid (13.93 mL, 13.93 mmol) in MeOH (150 mL) wasstirred under hydrogen atmosphere (4 atm) at room temperature for 1.5hr. The catalyst was removed by filtration, and the filtrate wasconcentrated under reduced pressure. The obtained residue was dissolvedin ethyl acetate, and the organic layer was washed with 1N aqueoussodium hydroxide solution and brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 5→20% ethyl acetate/hexane) to give4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluoroaniline(1.720 g, 6.48 mmol, 93%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.41 (6H, t, J=2.3 Hz), 3.51-3.85 (6H, m),5.79 (1H, s), 6.07-6.20 (2H, m).

(Step 3)

T3P (5.66 mL, 9.61 mmol) was added to a mixture of2-(tert-butoxycarbonyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (1030 mg, 3.20 mmol),4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluoroaniline (850mg, 3.20 mmol), DIEA (2.80 mL, 16.02 mmol) and DMAP (391 mg, 3.20 mmol)in ethyl acetate (30 mL), and the mixture was stirred overnight at 60°C. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 3→40% ethyl acetate/hexane), andcrystallized from ethyl acetate/hexane to give tert-butyl1-((4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(1190 mg, 2.093 mmol, 65.3%) as a white solid.

¹H NMR (300 MHz, CDCl₃)d 1.35-1.46 (9H, m), 1.51 (9H, s), 2.71-2.98 (2H,m), 3.50-3.78 (6H, m), 4.03 (2H, q, J=7.2 Hz), 5.41-6.03 (2H, m), 6.72(1H, s), 6.80 (1H, dd, J=8.5, 2.5 Hz), 6.97-7.10 (2H, m), 7.15 (1H,brs), 8.94 (1H, brs).

(Step 4)

tert-Butyl1-((4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.05 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.49 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-1-((4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.48 g, 97.9% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALCEL OD (NL001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 5)

4N Hydrogen chloride/ethyl acetate (4 mL) was added to a solution oftert-butyl(R)-1-((4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.49 g, 0.86 mmol) in ethyl acetate (2 mL), and the mixture was stirredovernight at room temperature. The precipitate was collected byfiltration with ethyl acetate/hexane to give(R)—N-(4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (0.392 g, 0.776 mmol, 90%) as a white solid.

MS(API): Calculated 504.9. Found 469.4 (M−HCl+H).

(Step 6)

Dihydro-2H-pyran-2,6(3H)-dione (9.72 mg, 0.09 mmol) was added to asolution of(R)—N-(4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (43 mg, 0.09 mmol) and TEA (0.024 mL, 0.17 mmol) in THF (4mL) at room temperature, and the mixture was stirred at 60° C. for 3 hr.The reaction mixture was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(solvent gradient; 5→100% ethyl acetate/hexane) to give the titlecompound (35.0 mg, 0.060 mmol, 70.5%) as a white solid.

¹H NMR (300 MHz, DMSO-d): δ 1.30 (3H, t, J=7.0 Hz), 1.36 (6H, s),1.66-1.81 (2H, m), 2.17-2.31 (4H, m), 2.71-2.86 (1H, m), 3.11 (1H, dt,J=15.6, 4.7 Hz), 3.45-3.55 (1H, m), 3.55-3.71 (4H, m), 4.00 (3H, q,J=7.2 Hz), 5.51-5.63 (1H, m), 5.80-6.31 (1H, m), 6.76-6.84 (2H, m),7.11-7.26 (2H, m), 7.43 (1H, d, J=9.1 Hz), 10.65 (1H, s), 12.04 (1H,brs).

Example 154(1R)—N-(4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)-6-ethoxy-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

HATU (45.2 mg, 0.12 mmol) was added to a solution of(R)—N-(4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (50 mg, 0.10 mmol), DIEA (0.042 mL, 0.24 mmol) and3-hydroxyisoxazole-5-carboxylic acid (15.34 mg, 0.12 mmol) in DMF (4 mL)at room temperature, and the mixture was stirred at room temperature for2 hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 5→90% ethyl acetate/hexane), and thensilica gel column chromatography (Diol, solvent gradient; 0→10%MeOH/ethyl acetate) to give the title compound (50.0 mg, 0.086 mmol,87%) as a white solid.

¹H NMR (300 MHz, DMSO-d): δ 1.30 (3H, t, J=7.0 Hz), 1.37 (6H, s),2.76-2.93 (1H, m), 3.04-3.21 (1H, m), 3.51-3.80 (5H, m), 4.01 (2H, q,J=7.1 Hz), 4.09-4.23 (1H, m), 5.53-5.69 (1H, m), 5.83-6.29 (1H, m), 6.58(1H, s), 6.73-6.89 (2H, m), 7.08-7.26 (2H, m), 7.42-7.56 (1H, m),10.45-10.93 (1H, m), 11.76 (1H, brs).

Example 155(1R)—N-(4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)-6-ethoxy-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

HATU (38.0 mg, 0.10 mmol) was added to a solution of(R)—N-(4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (42 mg, 0.08 mmol), DIEA (0.035 mL, 0.20 mmol) and2-(3-hydroxyisoxazol-5-yl)acetic acid (14.28 mg, 0.10 mmol) in DMF (2mL) at room temperature, and the mixture was stirred overnight at roomtemperature. To the reaction mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (Diol, solvent gradient; 5→90% ethylacetate/hexane), and crystallized from ethyl acetate/hexane to give thetitle compound (28.0 mg, 0.047 mmol, 56.7%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 1.30 (3H, t, J=7.0 Hz), 1.36 (6H, s),2.71-2.88 (1H, m), 3.03-3.19 (1H, m), 3.50-3.72 (5H, m), 3.88-4.12 (5H,m), 5.61 (1H, s), 5.80-6.27 (2H, m), 6.75-6.87 (2H, m), 7.09-7.25 (2H,m, J=13.2 Hz), 7.45 (1H, d, J=9.4 Hz), 10.69 (1H, s), 11.10 (1H, s).

Example 1565-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxy-3-methyl-5-oxopentanoicacid

4-Hydroxy-4-methyldihydro-2H-pyran-2,6(3H)-dione (55.4 mg, 0.38 mmol)was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(100 mg, 0.26 mmol) and TEA (0.071 mL, 0.51 mmol) in THF (2.0 mL) atroom temperature, and the mixture was stirred at room temperature for 3hr. The reaction mixture was concentrated under reduced pressure, andthe obtained residue was purified by silica gel column chromatography(solvent gradient; 50→100% ethyl acetate/hexane) to give the titlecompound (47.0 mg, 0.088 mmol, 34.3%) as a pale yellow solid.

Example 157(1R)—N-(4-(1-(cyclopropylmethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

Sodium hydride (60% oil, 7.64 g, 50.96 mmol) was added to a solution of2-(4-(bis(4-methoxybenzyl)amino)-2,6-difluorophenyl)-2-methylpropan-1-ol(3.0 g, 6.79 mmol), (bromomethyl)cyclopropane (1.647 mL, 16.99 mmol) andsodium iodide (7.64 g, 50.96 mmol) in DMF (9 mL) at 5° C., and themixture was stirred at 5° C. for 4 hr. DMF (3 mL) was added againthereto, and the mixture was stirred at room temperature for 14 hr. Tothe reaction mixture was added aqueous ammonium chloride solution, andthe mixture was extracted twice with ethyl acetate. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 5→20% ethylacetate/hexane) to give4-(1-(cyclopropylmethoxy)-2-methylpropan-2-yl)-3,5-difluoro-N,N-bis(4-methoxybenzyl)aniline(3.38 g, 6.82 mmol, 100%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 0.01 (2H, dd, J=4.9, 1.1 Hz), 0.32 (2H, dd,J=8.3, 1.5 Hz), 0.80-0.94 (1H, m), 1.28 (6H, t, J=2.1 Hz), 3.13 (2H, d,J=6.8 Hz), 3.44 (2H, s), 3.67 (6H, s), 4.34 (4H, s), 6.04 (2H, d, J=14.4Hz), 6.69-6.79 (4H, m), 6.98 (4H, d, J=8.7 Hz).

(Step 2)

A solution of4-(1-(cyclopropylmethoxy)-2-methylpropan-2-yl)-3,5-difluoro-N,N-bis(4-methoxybenzyl)aniline(1.03 g, 2.62 mmol), 1N hydrochloric acid (5.25 mL) and 10%palladium-carbon (0.558 g, 0.26 mmol, 50% wet) in MeOH (50 mL) wasstirred under hydrogen atmosphere (4 atm) at room temperature for 1.5hr. Separately, a solution of4-(1-(cyclopropylmethoxy)-2-methylpropan-2-yl)-3,5-difluoro-N,N-bis(4-methoxybenzyl)aniline(2.03 g, 4.10 mmol), 1N hydrochloric acid (8.19 mL) and 10%palladium-carbon (0.872 g, 0.41 mmol, 50% wet) in MeOH (100 mL) wasstirred under hydrogen atmosphere (4 atm) at room temperature for 1.5hr. The catalyst contained in each solution was removed by filtration,and the filtrates were concentrated under reduced pressure. The obtainedresidue was dissolved in ethyl acetate, the solution was washed with 1Naqueous sodium hydroxide solution and brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent gradient; 5→20% ethyl acetate/hexane) to give4-(1-(cyclopropylmethoxy)-2-methylpropan-2-yl)-3,5-difluoroaniline(1.810 g, 7.09 mmol, 105%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃)d −0.04-0.06 (2H, m), 0.26-0.38 (2H, m),0.76-0.94 (1H, m), 1.28 (6H, t, J=2.3 Hz), 3.12 (2H, d, J=6.8 Hz), 3.44(2H, s), 3.47-3.70 (2H, m), 5.90-6.06 (2H, m).

(Step 3)

T3P (6.22 mL, 10.58 mmol) was added to a solution of4-(1-(cyclopropylmethoxy)-2-methylpropan-2-yl)-3,5-difluoroaniline (900mg, 3.53 mmol),2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (1192 mg, 3.88 mmol), DMAP (474 mg, 3.88 mmol) and DIEA (3.08 mL,17.63 mmol) in ethyl acetate (30 mL), and the mixture was stirred at 80°C. for 2 hr. To the reaction mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent; ethyl acetate/hexane) to give tert-butyl1-((4-(1-(cyclopropylmethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(994.1 mg, 1.825 mmol, 51.8%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.07-0.16 (2H, m), 0.37-0.49 (2H, m),0.85-1.05 (1H, m), 1.42 (6H, t, J=2.3 Hz), 1.52 (9H, s), 2.75-2.99 (2H,m), 3.23 (2H, d, J=6.4 Hz), 3.51-3.74 (4H, m), 3.80 (3H, s), 5.57 (1H,brs), 6.72 (1H, d, J=2.3 Hz), 6.80 (1H, dd, J=8.3, 2.3 Hz), 6.94-7.09(2H, m), 7.19 (1H, brs), 9.01 (1H, brs).

(Step 4)

tert-Butyl1-((4-(1-(cyclopropylmethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.70 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((4-(1-(cyclopropylmethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.29 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-1-((4-(1-(cyclopropylmethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.30 g, >99% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALCEL OD (NL001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 5)

Cooled TFA (3.0 mL) was added to tert-butyl(R)-1-((4-(1-(cyclopropylmethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(294 mg, 0.54 mmol), and the mixture was stirred at room temperature for2 min. The reaction mixture was added to ice and aqueous sodium hydrogencarbonate solution, and the mixture was extracted three times with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reduced pressureto give(R)—N-(4-(1-(cyclopropylmethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(239.2 mg, 0.538 mmol, 100%) as a white solid.

MS(API): Calculated 444.5. Found 443.2 (M−H).

(Step 6)

HATU (82 mg, 0.22 mmol) was added to a solution of(R)—N-(4-(1-(cyclopropylmethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(80 mg, 0.18 mmol), DIEA (0.062 mL, 0.36 mmol) and2-(3-hydroxyisoxazol-5-yl)acetic acid (30.9 mg, 0.22 mmol) in DMF (2.0mL) at room temperature, and the mixture was stirred at room temperaturefor 2 hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→50% ethyl acetate/hexane), andcrystallized from ethyl acetate/hexane to give the title compound (33.3mg, 0.058 mmol, 32.5%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 0.03-0.11 (2H, m), 0.31-0.44 (2H, m),0.81-0.96 (1H, m), 1.36 (6H, s), 2.76-2.90 (1H, m), 3.03-3.22 (3H, m),3.43-3.65 (3H, m), 3.73 (3H, s), 3.88-4.17 (3H, m), 5.56-5.73 (1H, m),5.82-5.95 (1H, m), 6.77-6.91 (2H, m), 7.09-7.24 (2H, m), 7.47 (1H, d,J=9.1 Hz), 10.61-10.74 (1H, m), 11.13 (1H, brs).

Example 158(1R)—N-(4-(1-(cyclopropylmethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

HATU (82 mg, 0.22 mmol) was added to a solution of(R)—N-(4-(1-(cyclopropylmethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(80 mg, 0.18 mmol), DIEA (0.062 mL, 0.36 mmol) and3-hydroxyisoxazole-5-carboxylic acid (27.9 mg, 0.22 mmol) in DMF (2.0mL) at room temperature, and the mixture was stirred at room temperaturefor 2 hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→50% ethyl acetate/hexane) to givethe title compound (39.2 mg, 0.071 mmol, 39.2%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 0.04-0.14 (2H, m), 0.32-0.44 (2H, m),0.78-0.97 (1H, m), 1.37 (6H, s), 2.81-2.94 (1H, m), 3.02-3.24 (3H, m),3.52 (2H, s), 3.63-3.84 (4H, m), 4.09-4.24 (1H, m), 5.51-5.73 (1H, m),6.35-6.64 (1H, m), 6.76-6.92 (2H, m), 7.07-7.28 (2H, m), 7.45-7.58 (1H,m), 10.39-10.89 (1H, m), 11.80 (1H, brs).

Example 159(1R)—N-(4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

T3P (5.66 mL, 9.61 mmol) was added to a solution of4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluoroaniline (850mg, 3.20 mmol),2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (1083 mg, 3.53 mmol), DMAP (431 mg, 3.53 mmol) and DIEA (2.80 mL,16.02 mmol) in ethyl acetate (30 mL), and the mixture was stirred at 80°C. for 2 hr. To the reaction mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent; ethyl acetate/hexane) to give tert-butyl1-((4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(757.3 mg, 1.366 mmol, 42.6%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.42 (6H, t, J=2.1 Hz), 1.52 (9H, s),2.76-2.98 (2H, m), 3.51-3.75 (6H, m), 3.80 (3H, s), 5.35-5.99 (2H, m),6.73 (1H, d, J=2.3 Hz), 6.81 (1H, dd, J=8.3, 2.3 Hz), 6.97-7.10 (2H, m),7.18 (1H, brs), 9.03 (1H, brs).

(Step 2)

tert-Butyl1-((4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.80 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.34 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-1-((4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.34 g, >99% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALCEL OD (NL001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

Cooled TFA (3.0 mL) was added to tert-butyl(R)-1-((4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(337 mg, 0.61 mmol), and the mixture was stirred at room temperature for2 min. The reaction mixture was added to ice and aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theprecipitate was washed with hexane to give(R)—N-(4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(264.6 mg, 0.582 mmol, 96%) as white crystals.

MS(API): Calculated 454.5. Found 455.3 (M+H).

(Step 4)

HATU (80 mg, 0.21 mmol) was added to a solution of(R)—N-(4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(80 mg, 0.18 mmol), DIEA (0.060 mL, 0.35 mmol) and2-(3-hydroxyisoxazol-5-yl)acetic acid (30.2 mg, 0.21 mmol) in DMF (2.0mL) at room temperature, and the mixture was stirred at room temperaturefor 2 hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→50% ethyl acetate/hexane), andcrystallized from ethyl acetate/hexane to give the title compound (22.8mg, 0.039 mmol, 22.35%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 1.36 (6H, s), 2.70-2.90 (1H, m), 3.02-3.20(1H, m), 3.53-3.70 (5H, m), 3.73 (3H, s), 3.90-4.14 (3H, m), 5.55-5.70(1H, m), 5.82-6.27 (2H, m), 6.78-6.88 (2H, m), 7.12-7.24 (2H, m), 7.47(1H, d, J=9.4 Hz), 10.63-10.72 (1H, m), 11.12 (1H, brs).

Example 160(1R)—N-(4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

HATU (80 mg, 0.21 mmol) was added to a solution of(R)—N-(4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(80 mg, 0.18 mmol), DIEA (0.060 mL, 0.35 mmol) and3-hydroxyisoxazole-5-carboxylic acid (27.3 mg, 0.21 mmol) in DMF (2.0mL) at room temperature, and the mixture was stirred at room temperaturefor 2 hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→50% ethyl acetate/hexane) to givethe title compound (31.3 mg, 0.055 mmol, 31.4-) as a white solid.

¹H NMR (300 MHz, DMSO-d): δ 1.37 (6H, s), 2.81-2.95 (2H, m), 3.04-3.22(1H, m), 3.56-3.70 (4H, m), 3.74 (3H, s), 4.09-4.24 (1H, m), 5.54-5.70(1H, m), 5.82-6.29 (1H, m), 6.37-6.64 (1H, m), 6.80-6.93 (2H, m),7.11-7.28 (2H, m), 7.47-7.57 (1H, m), 10.42-10.88 (1H, m), 11.67-11.83(1H, m).

Example 1615-((1R)-1-((4-(1-(cyclopropylmethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

Dihydro-2H-pyran-2,6(3H)-dione (30.8 mg, 0.27 mmol) was added to asolution of(R)—N-(4-(1-(cyclopropylmethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(80 mg, 0.18 mmol) and TEA (0.050 mL, 0.36 mmol) in THF (2.0 mL) at roomtemperature, and the mixture was stirred at room temperature for 3 hr.The reaction mixture was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(solvent gradient; 50→100% ethyl acetate/hexane) to give the titlecompound (43.3 mg, 0.078 mmol, 43.1%) as a colorless oil.

¹H NMR (300 MHz, DMSO-d₆): δ 0.03-0.15 (2H, m), 0.30-0.48 (2H, m),0.77-1.00 (1H, m), 1.36 (6H, brs), 1.63-1.84 (2H, m), 2.16-2.35 (3H, m),2.38-2.62 (1H, m), 2.71-2.89 (1H, m), 3.18 (3H, d, J=6.4 Hz), 3.43-3.57(3H, m), 3.73 (3H, s), 3.94-4.11 (1H, m), 5.51-5.65 (1H, m), 6.76-6.88(2H, m), 7.07-7.26 (2H, m), 7.46 (1H, d, J=9.4 Hz), 10.55-10.71 (1H, m).

Example 1625-((1R)-1-((4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

Dihydro-2H-pyran-2,6(3H)-dione (30.1 mg, 0.26 mmol) was added to asolution of(R)—N-(4-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(80 mg, 0.18 mmol) and TEA (0.049 mL, 0.35 mmol) in THF (2.0 mL) at roomtemperature, and the mixture was stirred at room temperature for 3 hr.The reaction mixture was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(solvent gradient; 50→100% ethyl acetate/hexane) to give the titlecompound (62.9 mg, 0.111 mmol, 62.8%) as a colorless oil.

¹H NMR (300 MHz, DMSO-d): δ 1.36 (6H, brs), 1.64-1.84 (2H, m), 2.19-2.34(2H, m), 2.37-2.64 (2H, m), 2.71-2.89 (1H, m), 3.10-3.20 (1H, m),3.44-3.55 (1H, m), 3.56-3.69 (4H, m), 3.73 (3H, s), 3.96-4.10 (1H, m),5.54-5.64 (1H, m), 5.82-6.28 (1H, m), 6.76-6.88 (2H, m), 7.12-7.26 (2H,m), 7.46 (1H, d, J=9.4 Hz), 10.57-10.72 (1H, m).

Example 163(1R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-ethoxy-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

T3P (9.88 mL, 16.80 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (1.8 g, 5.60 mmol),3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)aniline (1.206 g, 5.60mmol), DIEA (4.89 mL, 28.01 mmol) and DMAP (0.684 g, 5.60 mmol) in ethylacetate (5 mL), and the mixture was stirred overnight at 60° C. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with 10% aqueous citric acidsolution, aqueous sodium hydrogen carbonate solution and brine, anddried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 3→50% ethyl acetate/hexane) to givetert-butyl1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(2.380 g, 4.59 mmol, 82%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.38-1.44 (9H, m), 1.51 (9H, s), 2.71-2.99(2H, m), 3.30 (3H, s), 3.51 (2H, s), 3.54-3.76 (2H, m), 4.03 (2H, q,J=6.8 Hz), 5.55 (1H, brs), 6.72 (1H, s), 6.80 (1H, dd, J=8.5, 2.5 Hz),7.03 (2H, d, J=12.5 Hz), 7.14 (1H, brs), 8.89 (1H, s).

(Step 2)

tert-Butyl1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(2.20 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.02 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.03 g, 98.7% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALCEL OD (NL001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

4N Hydrogen chloride/ethyl acetate (5 mL) was added to a solution oftert-butyl(R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.02 g, 1.97 mmol) in ethyl acetate (2 mL), and the mixture was stirredovernight at room temperature. The reaction mixture was concentratedunder reduced pressure, and the precipitate was collected by filtrationwith hexane to give(R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (0.917 g, 2.016 mmol, 102%) as a white solid.

MS(API): Calculated 454.9. Found 419.4 (M−HCl+H).

(Step 4)

HATU (47.1 mg, 0.12 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (47 mg, 0.10 mmol), DIEA (0.043 mL, 0.25 mmol) and3-hydroxyisoxazole-5-carboxylic acid (16.00 mg, 0.12 mmol) in DMF (4 mL)at room temperature, and the mixture was stirred at room temperature for2 hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate.

The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent gradient; 5→90% ethyl acetate/hexane) to give the titlecompound (40.0 mg, 0.076 mmol, 73.1%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 1.30 (3H, t, J=6.8 Hz), 1.36 (6H, s),2.80-2.89 (1H, m), 3.12 (1H, d, J=9.4 Hz), 3.19 (3H, s), 3.45 (2H, s),3.73 (1H, t, J=9.1 Hz), 4.01 (2H, q, J=6.9 Hz), 4.10-4.22 (1H, m), 5.64(1H, s), 6.59 (1H, s), 6.78-6.90 (2H, m), 7.09-7.25 (2H, m), 7.49 (1H,d, J=9.4 Hz), 10.81 (1H, s), 11.75 (1H, s).

Example 1645-((1R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

Dihydro-2H-pyran-2,6(3H)-dione (12.29 mg, 0.11 mmol) was added to asolution of(R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (49 mg, 0.11 mmol) and TEA (0.030 mL, 0.22 mmol) in THF (4mL) at room temperature, and the mixture was stirred at 60° C. for 2 hr.The reaction mixture was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(solvent gradient; 5→100% ethyl acetate/hexane) to give the titlecompound (25.00 mg, 0.047 mmol, 43.6%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 1.30 (3H, t, J=7.0 Hz), 1.35 (6H, s),1.63-1.82 (2H, m), 2.17-2.31 (2H, m), 2.38-2.60 (2H, m), 2.70-2.86 (1H,m), 3.03-3.16 (1H, m), 3.19 (3H, s), 3.40-3.57 (3H, m), 3.88-4.07 (3H,m), 5.60 (1H, s), 6.70-6.88 (2H, m), 7.05-7.25 (2H, m), 7.43 (1H, d,J=9.4 Hz), 10.64 (1H, s), 12.03 (1H, brs).

Example 165(1R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-ethoxy-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

HATU (43.1 mg, 0.11 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (43 mg, 0.09 mmol), DIEA (0.040 mL, 0.23 mmol) and2-(3-hydroxyisoxazol-5-yl)acetic acid (16.23 mg, 0.11 mmol) in DMF (4mL) at room temperature, and the mixture was stirred at room temperaturefor 2 hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 20→100% ethyl acetate/hexane) togive the title compound (22.00 mg, 0.040 mmol, 42.8%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 1.30 (3H, t, J=6.8 Hz), 1.35 (6H, s),2.75-2.90 (1H, m), 3.05-3.24 (4H, m), 3.44 (2H, s), 3.52-3.66 (1H, m),3.91-4.14 (5H, m), 5.61 (1H, s), 5.90 (1H, s), 6.75-6.89 (2H, m),7.06-7.24 (2H, m, J=13.2 Hz), 7.45 (1H, d, J=9.1 Hz), 10.69 (1H, s),11.10 (1H, s).

Example 1665-((1R)-6-ethoxy-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid (Step 1)

Sodium hydride (60% oil, 1.726 g, 43.15 mmol) was added to a solution of2-(4-(bis(4-methoxybenzyl)amino)-2,6-difluorophenyl)-2-methylpropan-1-ol(7.62 g, 17.26 mmol) and iodoethane (3.49 mL, 43.15 mmol) in DMF (30 mL)at 5° C., and the mixture was stirred at room temperature for 14 hr. Tothe reaction mixture was added aqueous ammonium chloride solution, andthe mixture was extracted twice with ethyl acetate. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (Diol, solvent gradient; 5→20% ethylacetate/hexane) to give4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluoro-N,N-bis(4-methoxybenzyl)aniline(8.51 g, 18.12 mmol, 105%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.14 (3H, t, J=7.0 Hz), 1.39 (6H, t, J=2.1Hz), 3.47 (2H, d, J=7.2 Hz), 3.53 (2H, s), 3.79 (6H, s), 4.46 (4H, s),6.17 (2H, d, J=14.4 Hz), 6.79-6.91 (4H, m), 7.11 (4H, d, J=8.7 Hz).

(Step 2)

A solution of4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluoro-N,N-bis(4-methoxybenzyl)aniline(8.51 g, 18.12 mmol), 1N hydrochloric acid (36.2 mL) and 10%palladium-carbon (1.929 g, 0.91 mmol, 50% wet) in MeOH (164 mL) wasstirred under hydrogen atmosphere (4 atm) at room temperature for 1.5hr. The catalyst was filtered off, and the filtrate was concentratedunder reduced pressure. The obtained residue was dissolved in ethylacetate, and the solvent was washed with 1N aqueous sodium hydroxidesolution and brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 5→20% ethylacetate/hexane) to give4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluoroaniline (3.87 g, 16.88mmol, 93%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.13 (3H, t, J=7.0 Hz), 1.40 (6H, t, J=2.5Hz), 3.40-3.50 (2H, m, J=7.2, 7.2, 7.2 Hz), 3.53 (2H, s), 3.57-3.87 (2H,m), 6.09 (1H, s), 6.13 (1H, s).

(Step 3)

T3P (4.62 mL, 7.85 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (841 mg, 2.62 mmol),4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluoroaniline (600 mg, 2.62mmol), DIEA (2.285 mL, 13.09 mmol) and DMAP (320 mg, 2.62 mmol) in ethylacetate (5 mL), and the mixture was stirred overnight at 60° C. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 3→950% ethyl acetate/hexane), andcrystallized from ethyl acetate/hexane to give tert-butyl6-ethoxy-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(700 mg, 1.314 mmol, 50.2%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 1.10 (3H, t, J=7.0 Hz), 1.36-1.45 (9H, m),1.51 (9H, s), 2.76-2.98 (2H, m), 3.44 (2H, q, J=6.8 Hz), 3.54 (3H, s),3.62-3.78 (1H, m), 4.03 (2H, q, J=6.8 Hz), 5.55 (1H, brs), 6.71 (1H, d,J=2.3 Hz), 6.80 (1H, dd, J=8.3, 2.6 Hz), 6.95-7.08 (2H, m, J=12.5 Hz),7.10-7.22 (1H, m), 8.92 (1H, s).

(Step 4)

tert-Butyl6-ethoxy-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.70 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-6-ethoxy-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.32 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-6-ethoxy-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.32 g, 92.2% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALPAK IA (QK001) 50 mmID×500 mmL

solvent: hexane/EtOH=850/150

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 5)

4N Hydrogen chloride/ethyl acetate (4 mL) was added to a solution oftert-butyl(R)-6-ethoxy-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(320 mg, 0.60 mmol) in ethyl acetate (2 mL), and the mixture was stirredovernight at room temperature. The reaction mixture was concentratedunder reduced pressure, and the precipitate was collected by filtrationwith hexane to give(R)-6-ethoxy-N-(4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (273 mg, 0.582 mmol, 97%) as a white solid.

MS(API): Calculated 468.96. Found 433.4 (M−HCl+H).

(Step 6)

Dihydro-2H-pyran-2,6(3H)-dione (83 mg, 0.73 mmol) was added to asolution of(R)-6-ethoxy-N-(4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (285 mg, 0.61 mmol) and TEA (0.102 mL, 0.73 mmol) in THF(5 mL) at room temperature, and the mixture was stirred at 60° C. for 1hr. The reaction mixture was concentrated under reduced pressure, andthe obtained residue was purified by silica gel column chromatography(solvent gradient; 10→100% ethyl acetate/hexane) to give the titlecompound (308 mg, 0.563 mmol, 93%) as a white solid.

¹H NMR (300 MHz, DMSO-d): δ 1.01 (3H, t, J=7.0 Hz), 1.30 (3H, t, J=7.0Hz), 1.35 (6H, s), 1.58-1.83 (2H, m), 2.18-2.32 (2H, m), 2.35-2.60 (2H,m), 2.74-2.88 (1H, m), 3.04-3.18 (1H, m), 3.37 (2H, q, J=7.2 Hz),3.44-3.58 (3H, m), 3.99 (3H, q, J=7.2 Hz), 5.60 (1H, s), 6.70-6.88 (2H,m), 7.09-7.26 (2H, m), 7.43 (1H, d, J=9.1 Hz), 10.64 (1H, s), 12.05 (1H,brs).

[α]_(D) ²⁵ −10.4 (c 0.251, MeOH)

Example 167(1R)-6-ethoxy-N-(4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

HATU (38.9 mg, 0.10 mmol) was added to a solution of(R)-6-ethoxy-N-(4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (40 mg, 0.09 mmol), DIEA (0.036 mL, 0.20 mmol) and3-hydroxyisoxazole-5-carboxylic acid (13.21 mg, 0.10 mmol) in DMF (4 mL)at room temperature, and the mixture was stirred at room temperature for2 hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 5→90% ethyl acetate/hexane) to givethe title compound (30.0 mg, 0.055 mmol, 64.7%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 1.02 (3H, t, J=7.0 Hz), 1.30 (3H, t, J=7.0Hz), 1.36 (6H, s), 2.78-2.94 (1H, m), 3.05-3.22 (1H, m), 3.35-3.42 (2H,m), 3.49 (2H, s), 3.62-3.80 (1H, m, J=8.7 Hz), 4.01 (2H, q, J=6.9 Hz),4.10-4.22 (1H, m), 5.64 (1H, s), 6.58 (1H, s), 6.78-6.90 (2H, m),7.11-7.24 (2H, m), 7.49 (1H, d, J=9.1 Hz), 10.80 (1H, s), 11.75 (1H, s).

Example 168(1R)-6-ethoxy-N-(4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

HATU (38.9 mg, 0.10 mmol) was added to a solution of(R)-6-ethoxy-N-(4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (40 mg, 0.09 mmol), DIEA (0.036 mL, 0.20 mmol) and2-(3-hydroxyisoxazol-5-yl)acetic acid (14.65 mg, 0.10 mmol) in DMF (4mL) at room temperature, and the mixture was stirred at room temperaturefor 2 hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (Diol, solvent gradient; 20→100% ethyl acetate/hexane),and solidified with ethyl acetate/hexane to give the title compound(15.00 mg, 0.027 mmol, 31.5%) as a white solid.

¹H NMR (300 MHz, DMSO-d): δ 1.01 (3H, t, J=7.0 Hz), 1.30 (3H, t, J=7.0Hz), 1.35 (6H, brs), 2.76-2.88 (1H, m), 3.05-3.19 (1H, m), 3.33-3.41(2H, m), 3.48 (2H, s), 3.52-3.64 (1H, m), 3.86-4.15 (5H, m), 5.61 (1H,s), 5.91 (1H, s), 6.76-6.88 (2H, m), 7.17 (2H, d, J=12.8 Hz), 7.45 (1H,d, J=9.1 Hz), 10.68 (1H, s), 11.10 (1H, s).

Example 169(1R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

HATU (273 mg, 0.72 mmol) was added to a solution of(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (251 mg, 0.60 mmol), DIEA (0.251 mL, 1.44 mmol) and2-(3-hydroxyisoxazol-5-yl)acetic acid (103 mg, 0.72 mmol) in DMF (4 mL)at room temperature, and the mixture was stirred at room temperature for2 hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 5→90% ethyl acetate/hexane) to givethe title compound (208 mg, 0.410 mmol, 68.4%) as a white solid.

¹H NMR (300 MHz, DMSO-d): δ 1.28 (6H, s), 1.86 (2H, t, J=7.4 Hz),2.79-2.92 (3H, m), 3.05-3.19 (1H, m), 3.31 (3H, s), 3.65 (1H, ddd,J=12.3, 8.3, 4.3 Hz), 3.86-4.17 (3H, m), 4.36 (2H, s), 5.74 (1H, s),5.84-5.96 (1H, m), 7.07-7.30 (4H, m), 7.54 (1H, d, J=7.9 Hz), 10.51 (1H,s), 11.11 (1H, s).

[α]_(D) ²⁵ +22.7 (c 0.2510, MeOH)

Example 170(1R)—N-(4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

T3P (4.62 mL, 7.85 mmol) was added to a solution of4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluoroaniline (600 mg, 2.62mmol),2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (885 mg, 2.88 mmol), DMAP (352 mg, 2.88 mmol) and DIEA (2.285 mL,13.09 mmol) in ethyl acetate (30 mL), and the mixture was stirred at 80°C. for 2 hr. To the reaction mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent; ethyl acetate/hexane), and thenpreparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1%TFA)) to give tert-butyl1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(644 mg, 1.242 mmol, 47.5%).

¹H NMR (300 MHz, CDCl₃): δ 1.10 (3H, t, J=7.2 Hz), 1.39-1.44 (6H, m),1.52 (9H, s), 2.78-2.97 (2H, m), 3.44 (2H, q, J=7.2 Hz), 3.51-3.74 (4H,m), 3.80 (3H, s), 5.56 (1H, brs), 6.69-6.76 (1H, m), 6.81 (1H, dd,J=8.3, 2.6 Hz), 6.96-7.09 (2H, m), 7.18 (1H, brs), 8.96 (1H, brs).

(Step 2)

tert-Butyl1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.45 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.19 g, >99′% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.20 g, >99% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALPAK IA (QK001) 50 mmID×500 mmL

solvent: hexane/EtOH=850/150

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

Cooled TFA (2.0 mL) was added to tert-butyl(R)-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(194 mg, 0.37 mmol), and the mixture was stirred at room temperature for2 min. The reaction mixture was added to ice and aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure to givecrude(R)—N-(4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(157 mg, 0.375 mmol, 100%) as a white solid.

MS(API): Calculated 418.5. Found 417.2 (M−H).

(Step 4)

HATU (54.5 mg, 0.14 mmol) was added to a solution of the crude(R)—N-(4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(50 mg, 0.12 mmol), DIEA (0.041 mL, 0.24 mmol) and2-(3-hydroxyisoxazol-5-yl)acetic acid (20.52 mg, 0.14 mmol) in DMF (2.0mL) at room temperature, and the mixture was stirred at room temperaturefor 2 hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 50→100% ethyl acetate/hexane), andrecrystallized from ethyl acetate/hexane to give the title compound(21.1 mg, 0.039 mmol, 32.5%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 1.01 (3H, t, J=7.0 Hz), 1.35 (6H, s),2.76-2.89 (1H, m), 3.05-3.20 (1H, m), 3.36 (2H, q, J=7.1 Hz), 3.48 (2H,s), 3.52-3.64 (1H, m), 3.73 (3H, s), 3.90-4.15 (3H, m), 5.56-5.70 (1H,m), 5.83-5.96 (1H, m), 6.76-6.88 (2H, m), 7.17 (2H, d, J=13.2 Hz), 7.47(1H, d, J=9.4 Hz), 10.68 (1H, s), 11.10 (1H, s).

Example 171(1R)—N-(4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

HATU (54.5 mg, 0.14 mmol) was added to a solution of(R)—N-(4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(50 mg, 0.12 mmol), DIEA (0.041 mL, 0.24 mmol) and3-hydroxyisoxazole-5-carboxylic acid (18.51 mg, 0.14 mmol) in DMF (2.0mL) at room temperature, and the mixture was stirred at room temperaturefor 2 hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 50→100% ethyl acetate/hexane, 0→10%MeOH/ethyl acetate), and solidified with ethyl acetate/hexane to givethe title compound (46.3 mg, 0.087 mmol, 73.2%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 1.02 (3H, t, J=7.0 Hz), 1.36 (6H, s),2.83-2.92 (1H, m), 3.06-3.22 (1H, m), 3.37 (2H, q, J=7.0 Hz), 3.49 (2H,s), 3.67-3.80 (4H, m), 4.11-4.22 (1H, m), 5.55-5.68 (1H, m), 6.41-6.62(1H, m), 6.81-6.91 (2H, m), 7.0-7.25 (2H, m), 7.48-7.58 (1H, m),10.43-10.85 (1H, m), 11.76 (1H, brs).

Example 1725-((1R)-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

Dihydro-2H-pyran-2,6(3H)-dione (297 mg, 2.60 mmol) was added to asolution of(R)—N-(4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(790 mg, 1.74 mmol) and TEA (0.726 mL, 5.21 mmol) in THF (15 mL) at roomtemperature, and the mixture was stirred at room temperature for 3 hr.The reaction mixture was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(solvent gradient; 50→100% ethyl acetate/hexane), and crystallized fromethyl acetate/hexane to give the title compound (568.1 mg, 1.067 mmol,61.4%) as white crystals.

[α]_(D) ²⁵ −3.3 (c 0.2530, MeOH)

Example 173(5R)—N-(4-(ethyl(dimethyl)silyl)-3,5-difluorophenyl)-6-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-2-(methoxymethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(Step 1)

T3P (32.8 mL, 55.73 mmol) was added to a solution of6-(tert-butoxycarbonyl)-2-(ethoxycarbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylicacid (7.16 g, 20.44 mmol), 4-(ethyldimethylsilyl)-3,5-difluoroaniline(4.0 g, 18.58 mmol), DMAP (2.497 g, 20.44 mmol) and DIEA (16.22 mL,92.89 mmol) in ethyl acetate (120 mL), and the mixture was stirred at80° C. for 2 hr. To the reaction mixture was added water, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent; ethyl acetate/hexane) togive 2-ethyl 6-tert-butyl5-((4-(ethyldimethylsilyl)-3,5-difluorophenyl)carbamoyl)-7,8-dihydro-1,6-naphthyridine-2,6(5H)-dicarboxylate(4.61 g, 8.42 mmol, 45.3%) as a grayish white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.31 (6H, t, J=1.5 Hz), 0.74-0.85 (2H, m),0.89-0.98 (3H, m), 1.43 (3H, t, J=7.0 Hz), 1.55 (9H, s), 3.11-3.22 (2H,m), 3.42-3.63 (1H, m), 4.05-4.14 (1H, m), 4.43-4.54 (2H, m), 5.76 (1H,brs), 6.97-7.06 (2H, m), 7.74 (1H, brs), 8.03 (1H, d, J=7.9 Hz), 9.11(1H, brs).

(Step 2)

Sodium borohydride (0.953 g, 25.20 mmol) was added to a solution of2-ethyl 6-tert-butyl5-((4-(ethyldimethylsilyl)-3,5-difluorophenyl)carbamoyl)-7,8-dihydro-1,6-naphthyridine-2,6(5H)-dicarboxylate(4.6 g, 8.40 mmol) and calcium chloride (1.398 g, 12.60 mmol) in a mixedsolvent of EtOH (45 mL) and THF (45 mL) at 0° C., and the mixture wasstirred at room temperature for 5 hr. To the reaction mixture was added1N hydrochloric acid, and the mixture was extracted with ethyl acetate.The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent; ethyl acetate/hexane) to give tert-butyl5-((4-(ethyldimethylsilyl)-3,5-difluorophenyl)carbamoyl)-2-(hydroxymethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.45 g, 2.87 mmol, 34.1%) as a colorless oil.

¹H NMR (300 MHz, CDCl₂): δ 0.25-0.35 (6H, m), 0.71-0.85 (2H, m),0.89-0.99 (3H, m), 1.55 (9H, s), 2.99-3.10 (2H, m), 3.52 (1H, brs), 3.75(1H, brs), 4.03-4.14 (1H, m), 4.74 (2H, s), 5.69 (1H, brs), 6.97-7.06(2H, m), 7.12-7.19 (1H, m), 7.61 (1H, brs), 9.13 (1H, brs).

(Step 3)

Methanesulfonyl chloride (0.444 mL, 5.74 mmol) was added to a solutionof tert-butyl5-((4-(ethyldimethylsilyl)-3,5-difluorophenyl)carbamoyl)-2-(hydroxymethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.45 g, 2.87 mmol) and TEA (0.799 mL, 5.74 mmol) in THF (30 mL) at 0°C., and the mixture was stirred at room temperature for 1 hr. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent; ethyl acetate/hexane) to give tert-butyl5-((4-(ethyldimethylsilyl)-3,5-difluorophenyl)carbamoyl)-2-(((methylsulfonyl)oxy)methyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.97 g, 3.37 mmol, 118%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 0.25-0.36 (6H, m), 0.72-0.85 (2H, m),0.88-1.00 (3H, m), 1.55 (9H, s), 2.92-3.16 (5H, m), 3.49 (1H, brs),4.02-4.16 (1H, m), 5.31 (2H, s), 5.72 (1H, brs), 6.96-7.07 (2H, m), 7.39(1H, d, J=7.9 Hz), 7.66 (1H, brs), 9.09 (1H, brs).

(Step 4)

A solution of tert-butyl5-((4-(ethyldimethylsilyl)-3,5-difluorophenyl)carbamoyl)-2-(((methylsulfonyl)oxy)methyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(1.80 g, 3.08 mmol) in MeOH (40 mL) was stirred overnight at 60° C., andthe reaction mixture was concentrated under reduced pressure. To asolution of the obtained residue in THF (40.0 mL) were added TEA (0.516mL, 3.70 mmol) and Boc₂O (0.859 mL, 3.70 mmol) at room temperature, andthe mixture was stirred at room temperature for 2 hr. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent; ethyl acetate/hexane), and then preparativeHPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)) togive tert-butyl5-((4-(ethyldimethylsilyl)-3,5-difluorophenyl)carbamoyl)-2-(methoxymethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(970 mg, 1.867 mmol, 60.5%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.31 (6H, t, J=1.5 Hz), 0.71-0.85 (2H, m),0.89-0.99 (3H, m), 1.54 (9H, s), 2.97-3.12 (2H, m), 3.43-3.62 (4H, m),4.00-4.15 (1H, m), 4.51-4.60 (2H, m), 5.68 (1H, brs), 6.95-7.07 (2H, m),7.33 (1H, d, J=7.9 Hz), 7.61 (1H, brs), 9.08 (1H, brs).

(Step 5)

tert-Butyl5-((4-(ethyldimethylsilyl)-3,5-difluorophenyl)carbamoyl)-2-(methoxymethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(0.72 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-5-((4-(ethyldimethylsilyl)-3,5-difluorophenyl)carbamoyl)-2-(methoxymethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(0.33 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-5-((4-(ethyldimethylsilyl)-3,5-difluorophenyl)carbamoyl)-2-(methoxymethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(0.33 g, >99% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALPAK IA (QK001) 50 mmID×500 mmL

solvent: hexane/EtOH=850/150

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 6)

Cooled TFA (3.0 mL) was added to tert-butyl(R)-5-((4-(ethyldimethylsilyl)-3,5-difluorophenyl)carbamoyl)-2-(methoxymethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(333 mg, 0.64 mmol), and the mixture was stirred at room temperature for2 min. The reaction mixture was added to ice and aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure to givecrude(R)—N-(4-(ethyldimethylsilyl)-3,5-difluorophenyl)-2-(methoxymethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(266.4 mg, 0.635 mmol, 99%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.22-0.38 (6H, m), 0.73-0.86 (2H, m),0.86-1.00 (3H, m), 2.84-3.11 (2H, m), 3.14-3.35 (2H, m), 3.46 (3H, s),4.47-4.60 (2H, m), 4.67 (1H, s), 7.02-7.14 (2H, m), 7.30 (1H, d, J=8.3Hz), 7.97 (1H, d, J=8.3 Hz), 9.63 (1H, brs).

(Step 7)

HATU (32.6 mg, 0.09 mmol) was added to a solution of(R)—N-(4-(ethyldimethylsilyl)-3,5-difluorophenyl)-2-(methoxymethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(30 mg, 0.07 mmol), DIEA (0.024 mL, 0.14 mmol) and2-(3-hydroxyisoxazol-5-yl)acetic acid (12.28 mg, 0.09 mmol) in DMF (2.0mL) at room temperature, and the mixture was stirred at room temperaturefor 4 hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→50% ethyl acetate/hexane), andrecrystallized from ethyl acetate/hexane to give (7.8 mg, 0.014 mmol,20.03%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 0.28 (6H, s), 0.68-0.80 (2H, m), 0.84-0.94(3H, m), 2.90-3.05 (1H, m), 3.08-3.22 (1H, m), 3.34 (3H, s), 3.81-3.95(1H, m), 3.96-4.20 (3H, m), 4.46 (2H, s), 5.80 (1H, s), 5.91 (1H, s),7.21 (2H, d, J=9.8 Hz), 7.28-7.38 (1H, m), 7.85-7.95 (1H, m),10.80-10.99 (1H, m), 11.12 (1H, brs).

Example 174(5R)—N-(4-(ethyl(dimethyl)silyl)-3,5-difluorophenyl)-6-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-2-(methoxymethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide

HATU (32.6 mg, 0.09 mmol) was added to a solution of(R)—N-(4-(ethyldimethylsilyl)-3,5-difluorophenyl)-2-(methoxymethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(30 mg, 0.07 mmol), DIEA (0.024 mL, 0.14 mmol) and3-hydroxyisoxazole-5-carboxylic acid (11.08 mg, 0.09 mmol) in DMF (2.0mL) at room temperature, and the mixture was stirred at room temperaturefor 4 hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 50→100% ethyl acetate/hexane) to givethe title compound (13.6 mg, 0.026 mmol, 35.8%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 0.29 (6H, s), 0.67-0.80 (2H, m), 0.84-0.95(3H, m), 2.92-3.12 (1H, m), 3.13-3.26 (1H, m), 3.35 (3H, s), 3.94-4.07(1H, m), 4.15-4.28 (1H, m), 4.47 (2H, s), 5.82 (1H, s), 6.61 (1H, s),7.23 (2H, d, J=9.4 Hz), 7.36 (1H, d, J=7.9 Hz), 7.96 (1H, d, J=7.9 Hz),10.63-11.20 (1H, m), 11.81 (1H, brs).

Example 1755-((5R)-5-((4-(ethyl(dimethyl)silyl)-3,5-difluorophenyl)carbamoyl)-2-(methoxymethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-oxopentanoicacid

Dihydro-2H-pyran-2,6(3H)-dione (12.24 mg, 0.11 mmol) was added to asolution of(R)—N-(4-(ethyldimethylsilyl)-3,5-difluorophenyl)-2-(methoxymethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(30 mg, 0.07 mmol) and TEA (0.020 mL, 0.14 mmol) in THF (8.0 mL) at roomtemperature, and the mixture was stirred at room temperature for 3 hr.The reaction mixture was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(solvent gradient; 50→100% ethyl acetate/hexane) to give the titlecompound (19.8 mg, 0.037 mmol, 51.9%) as a colorless oil.

¹H NMR (300 MHz, DMSO-d₆): δ 0.29 (6H, d, J=1.5 Hz), 0.68-0.80 (2H, m),0.84-0.95 (3H, m), 1.64-1.82 (2H, m), 2.18-2.37 (2H, m), 2.41-2.66 (2H,m), 2.87-3.21 (2H, m), 3.34 (3H, d, J=1.5 Hz), 3.74-3.88 (1H, m),3.97-4.12 (1H, m), 4.45 (2H, s), 5.79 (1H, s), 7.22 (2H, d, J=9.8 Hz),7.31 (1H, d, J=7.9 Hz), 7.90 (1H, d, J=7.9 Hz), 10.89 (1H, s), 11.49(1H, brs).

Example 1765-((1R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

Dihydro-2H-pyran-2,6(3H)-dione (220 mg, 1.93 mmol) was added to asolution of(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (520 mg, 1.28 mmol) (which can be synthesized in the samemanner as above) and TEA (0.537 mL, 3.85 mmol) in THF (10 mL) at roomtemperature, and the mixture was stirred at room temperature for 3 hr.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 50→100% ethyl acetate/hexane), andcrystallized from ethyl acetate/hexane to give the title compound (531.3mg, 1.101 mmol, 86%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 1.28 (6H, d, J=1.5 Hz), 1.63-1.81 (2H, m),1.86 (2H, t, J=7.4 Hz), 2.20-2.32 (2H, m), 2.35-2.62 (2H, m), 2.69-2.90(3H, m), 3.04-3.19 (1H, m), 3.45-3.60 (1H, m), 3.72 (3H, s), 3.92-4.08(1H, m), 5.53-5.69 (1H, m), 6.75-6.86 (2H, m), 7.12-7.27 (2H, m),7.41-7.52 (1H, m), 10.35-10.48 (1H, m), 12.05 (1H, brs).

[α]_(D) ²⁵ +2.7 (c 0.2535, MeOH)

Example 1774-((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-4-oxobutanoicacid

Succinic anhydride (58.8 mg, 0.59 mmol) was added to a solution of(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(167 mg, 0.45 mmol) and TEA (95 μL, 0.68 mmol) in THF (3.9 mL) at roomtemperature, and the mixture was stirred at room temperature for 15 hr.To the reaction mixture was added water, and 2N hydrochloric acid wasadded thereto until the pH of the mixture became 4. Then, the mixturewas extracted three times with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (Diol, solvent gradient; 30→100% ethylacetate/hexane) to give the title compound (162.0 mg, 0.345 mmol, 76%)as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.31 (6H, s), 1.87 (2H, t, J=7.4 Hz),2.69-2.93 (7H, m), 2.97-3.06 (2H, m), 3.72-3.83 (1H, m), 3.91 (3H, s),3.98 (1H, dt), 5.99 (1H, s), 6.63 (1H, d, J=8.7 Hz), 7.01-7.09 (2H, m),7.45 (1H, d, J=8.7 Hz), 8.81 (1H, s).

Example 1784-((5R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-4-oxobutanoicacid

Succinic anhydride (30.7 mg, 0.31 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(100 mg, 0.26 mmol) and TEA (0.071 mL, 0.51 mmol) in THF (2.0 mL) atroom temperature, and the mixture was stirred overnight at roomtemperature. To the reaction mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 50→100% ethyl acetate/hexane)to give the title compound (91.6 mg, 0.186 mmol, 73.0%) as a whitesolid.

¹H NMR (300 MHz, DMSO-d₆): δ 0.30 (9H, s), 2.43-2.54 (2H, m), 2.65-2.79(2H, m), 2.83-2.97 (1H, m), 3.00-3.13 (1H, m), 3.75-3.90 (4H, m),3.97-4.12 (1H, m), 5.66-5.76 (1H, m), 6.73 (1H, d, J=8.7 Hz), 7.15-7.29(2H, m), 7.70-7.81 (1H, m), 10.76 (1H, s), 12.08 (1H, brs).

Example 1795-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid (Step 1)

T3P (4.39 mL, 7.47 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (0.8 g, 2.49 mmol), 3,5-difluoro-4-(trimethylsilyl)aniline (0.501g, 2.49 mmol), DIEA (2.174 mL, 12.45 mmol) and DMAP (0.304 g, 2.49 mmol)in ethyl acetate (25 mL), and the mixture was stirred at 70° C. for 20hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 2→40% ethyl acetate/hexane) to givetert-butyl1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.110 g, 2.200 mmol, 88%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.26-0.36 (9H, m), 1.41 (3H, t, J=7.0 Hz),1.52 (9H, s), 2.66-2.95 (2H, m), 3.35-3.77 (2H, m), 4.03 (2H, q, J=7.2Hz), 5.56 (1H, brs), 6.72 (1H, s), 6.80 (1H, dd, J=8.3, 2.6 Hz), 7.02(2H, d, J=9.1 Hz), 7.09-7.22 (1H, m, J=8.3 Hz), 9.09 (1H, brs).

(Step 2)

tert-Butyl1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.09 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.436 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.441 g, >99% ee), each as a white solid.

purification condition by chiral column chromatography column CHIRALPAKIA 50 mmID×500 mmL

solvent: hexane/EtOH=950/50

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

Cooled TFA (6 mL) was added to tert-butyl(R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(436 mg, 0.86 mmol), and the mixture was stirred for 30 min under icewater. The reaction mixture was added to aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The organic layer was dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure to give(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(350 mg, 0.865 mmol, 100%) as a white gum-like substance.

MS(API): Calculated 404.5. Found 405.1 (M+H).

(Step 4)

Dihydro-2H-pyran-2,6(3H)-dione (26.7 mg, 0.23 mmol) was added to asolution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(63 mg, 0.16 mmol) and TEA (0.033 mL, 0.23 mmol) in THF (2 mL) at roomtemperature, and the mixture was stirred overnight at room temperature.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 10→90% ethyl acetate/hexane), andcrystallized from ethyl acetate/hexane to give the title compound (25.00mg, 0.048 mmol, 31.0%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 0.29 (9H, s), 1.30 (3H, t, J=7.0 Hz),1.59-1.83 (2H, m), 2.17-2.32 (3H, m), 2.38-2.61 (1H, m), 2.70-2.86 (1H,m), 3.04-3.18 (1H, m), 3.50 (1H, t, J=8.3 Hz), 3.91-4.07 (3H, m), 5.61(1H, s), 6.73-6.73-6.85 (2H, m), 7.20 (2H, d, J=9.8 Hz), 7.44 (1H, d,J=9.1 Hz), 10.76 (1H, s), 12.06 (1H, brs).

[α]_(D) ²⁵ −11.1 (c 0.2500, MeOH)

Example 1804-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutanoicacid

Succinic anhydride (30.4 mg, 0.30 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(82 mg, 0.20 mmol) and TEA (0.042 mL, 0.30 mmol) in THF (6 mL) at roomtemperature, and the mixture was stirred overnight at room temperature.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 20→90% ethyl acetate/hexane) to givethe title compound (1.0 mg, 0.121 mmol, 59.6%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 0.29 (9H, s), 1.30 (3H, t, J=7.0 Hz),2.40-2.48 (2H, m), 2.63-2.89 (3H, m), 3.05-3.22 (1H, m), 3.43-3.60 (1H,m), 3.94-4.09 (3H, m), 5.55-5.67 (1H, m), 6.72-6.88 (2H, m), 7.12-7.26(2H, m), 7.42 (1H, d, J=8.3 Hz), 10.72 (1H, s), 12.05 (1H, brs).

Example 1815-((1R)-6-((difluoromethoxy)methyl)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

Dihydro-2H-pyran-2,6(3H)-dione (22.15 mg, 0.19 mmol) was added to asolution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-((difluoromethoxy)methyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(57 mg, 0.13 mmol) (which can be synthesized in the same manner asabove) and TEA (0.027 mL, 0.19 mmol) in THF (6 mL) at room temperature,and the mixture was stirred overnight at room temperature. The reactionmixture was concentrated under reduced pressure. To the obtained residuewas added water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 10→90% ethyl acetate/hexane) to give the title compound (31.0mg, 0.056 mmol, 43.2%) as a white solid.

¹H NMR (300 MHz, DMSO-d): δ 0.30 (9H, s), 1.73 (2H, dq, J=15.0, 7.3 Hz),2.18-2.35 (3H, m), 2.38-2.61 (1H, m), 2.80-2.94 (1H, m), 3.04-3.22 (1H,m), 3.57 (1H, ddd, J=12.4, 8.4, 4.2 Hz), 3.96-4.10 (1H, m), 4.86 (2H,s), 5.71 (1H, s), 6.77 (1H, t, J=75.5 Hz), 7.15-7.31 (4H, m), 7.56 (1H,d, J=7.9 Hz), 10.83 (1H, s), 12.05 (1H, brs).

Example 1825-((1R)-6-ethoxy-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid (Step 1)

tert-Butyl6-ethoxy-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.786 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-6-ethoxy-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.367 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-6-ethoxy-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.358 g, 97.9% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALPAK IA 50 mmID×500 mmL

solvent: hexane/EtOH=950/50

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 2)

Cooled TFA (4.0 mL) was added to tert-butyl(R)-6-ethoxy-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(367 mg, 0.76 mmol), and the mixture was stirred at room temperature for2 min. The reaction mixture was added to ice and aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theprecipitate was washed with hexane to give(R)-6-ethoxy-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(272.3 mg, 0.712 mmol, 94%) as a white solid.

MS(API): Calculated 382.5. Found 383.3 (M+H).

(Step 3)

Dihydro-2H-pyran-2,6(3H)-dione (67.1 mg, 0.59 mmol) was added to asolution of(R)-6-ethoxy-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(150 mg, 0.39 mmol) and TEA (0.082 mL, 0.59 mmol) in THF (3.0 mL) atroom temperature, and the mixture was stirred overnight at roomtemperature. To the reaction mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (Diol, solvent gradient; 20→90% ethylacetate/hexane), and crystallized from ethyl acetate/hexane to give thetitle compound (130.7 mg, 0.263 mmol, 67.1%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 1.22-1.35 (9H, m), 1.66-1.80 (2H, m),1.82-1.91 (2H, m), 2.20-2.32 (2H, m), 2.35-2.61 (2H, m), 2.69-2.90 (3H,m), 3.03-3.18 (1H, m), 3.46-3.59 (1H, m), 3.93-4.07 (3H, m), 5.57-5.68(1H, m), 6.75-6.83 (2H, m), 7.12-7.27 (2H, m), 7.40-7.48 (1H, m),10.33-10.55 (1H, m), 12.05 (1H, brs).

Example 1835-((1R)-6-ethoxy-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid (Step 1)

T3P (5.78 mL, 9.82 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (1157 mg, 3.60 mmol), 3-fluoro-4-(trimethylsilyl)aniline (600 mg,3.27 mmol), DMAP (440 mg, 3.60 mmol) and DIEA (2.86 mL, 16.37 mmol) inethyl acetate (20 mL), and the mixture was stirred at 80° C. for 2 hr.To the reaction mixture was added water, and the mixture was extractedthree times with ethyl acetate. The organic layer was washed with 10%aqueous citric acid solution, aqueous sodium hydrogen carbonate solutionand brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was solidified with Et₂Oto give tert-butyl6-ethoxy-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(601.8 mg, 1.237 mmol, 37.8%) as a white solid.

MS(API): Calculated 486.7. Found 485.3 (M−H).

(Step 2)

tert-Butyl6-ethoxy-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.602 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-6-ethoxy-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.267 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-6-ethoxy-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.270 g, >99% ee), each as a white solid.

column: CHIRALPAK IA

solvent: hexane/EtOH=950/50

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

Cooled TFA (3.0 mL) was added to tert-butyl(R)-6-ethoxy-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(267 mg, 0.55 mmol), and the mixture was stirred at room temperature for2 min. The reaction mixture was added to ice and aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure to give(R)-6-ethoxy-N-(3-fluoro-4-(trimethylsilyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(211.9 mg, 0.548 mmol, 100%) as a white solid.

MS(API): Calculated 386.5. Found 387.3 (M+H).

(Step 4)

Dihydro-2H-pyran-2,6(3H)-dione (66.4 mg, 0.58 mmol) was added to asolution of(R)-6-ethoxy-N-(3-fluoro-4-(trimethylsilyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(150 mg, 0.39 mmol) and TEA (0.081 mL, 0.58 mmol) in THF (3.0 mL) atroom temperature, and the mixture was stirred overnight at roomtemperature. To the reaction mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (Diol, solvent gradient; 20→90% ethylacetate/hexane), and crystallized from ethyl acetate/hexane to give thetitle compound (93.8 mg, 0.187 mmol, 48.3%) as white crystals.

¹H NMR (300 MHz, DMSO-d): δ 0.25 (9H, s), 1.29 (3H, t, J=7.0 Hz), 1.74(2H, quin, J=7.2 Hz), 2.18-2.32 (2H, m), 2.35-2.61 (2H, m), 2.70-2.87(1H, m), 3.04-3.20 (1H, m), 3.44-3.58 (1H, m), 3.93-4.07 (3H, m),5.59-5.69 (1H, m), 6.75-6.84 (2H, m), 7.24-7.37 (2H, m), 7.41-7.50 (2H,m), 10.53-10.71 (1H, m), 12.04 (1H, brs).

Example 1845-((1R)-1-((2,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid (Step 1)

Nitric acid (d 1.42) (26.2 g, 286.81 mmol) was slowly added dropwise toconc. sulfuric acid (102 g, 1042.96 mmol) over 1 hr under ice water,while the mixture was maintained at 10° C. or below. Then,2-bromo-1,4-difluorobenzene (50.32 g, 260.74 mmol) was slowly addedthereto over 3 hr while the mixture was maintained at 10° C. or below.The reaction mixture was stirred at 5° C. for 30 min, and then at roomtemperature for 1 hr. The reaction mixture was poured into ice (about600 g), and the mixture was extracted three times with a mixed solventof Et₂O/THF (3:1). The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent; 20% ethyl acetate/hexane) to give1-bromo-2,5-difluoro-4-nitrobenzene (49.64 g, 209 mmol, 80%) as a paleyellow solid.

¹H NMR (300 MHz, CDCl₃): δ 7.59 (1H, dd, J=9.4, 5.3 Hz), 7.89 (1H, dd,J=7.2, 6.4 Hz).

(Step 2)

Hexamethyldisilane (34.4 mL, 167.91 mmol) was added to a solution of1-bromo-2,5-difluoro-4-nitrobenzene (10.8 g, 45.38 mmol) and Pd(Ph3P)₄(1.311 g, 1.13 mmol) in xylene (15 mL), and the mixture was stirred at140° C. for 2 days under argon gas atmosphere. The reaction mixture wascooled. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent; ethyl acetate/hexane) to give(2,5-difluoro-4-nitrophenyl)trimethylsilane (2.44 g, 10.55 mmol, 23.25%)as a yellow oil.

(Step 3)

A solution of (2,5-difluoro-4-nitrophenyl)trimethylsilane (2.44 g, 10.55mmol) and 10% palladium-carbon (650 mg, 6.11 mmol, 50% wet) in MeOH (50mL) was stirred under hydrogen atmosphere (1 atm) at room temperaturefor 5 hr. The catalyst was filtered off, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (NH, solvent; ethyl acetate/hexane)to give 2,5-difluoro-4-(trimethylsilyl)aniline (1.11 g, 5.51 mmol,52.3%) as a yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 0.26 (9H, d, J=1.1 Hz), 3.84 (2H, brs), 6.40(1H, dd, J=9.1, 6.8 Hz), 6.86-6.95 (1H, m).

(Step 4)

T3P (3.51 mL, 5.96 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (702 mg, 2.19 mmol), 2,5-difluoro-4-(trimethylsilyl)aniline (400mg, 1.99 mmol), DMAP (267 mg, 2.19 mmol) and DIEA (1.735 mL, 9.94 mmol)in ethyl acetate (10 mL), and the mixture was stirred at 80° C. for 2hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→10% ethyl acetate/hexane), andsolidified with Et₂O/hexane to give tert-butyl1-((2,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(239.3 mg, 0.474 mmol, 23.86%) as a white solid.

MS(API): Calculated 504.6. Found 503.3 (M+H).

(Step 5)

tert-Butyl1-((2,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.239 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((2,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.088 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-1-((2,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.112 g, >99% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALPAK IA 50 mmID×500 mmL

solvent: hexane/EtOH=950/50

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 6)

Cooled TFA (2.0 mL) was added to tert-butyl(R)-1-((2,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(80 mg, 0.16 mmol), and the mixture was stirred at room temperature for2 min. The reaction mixture was added to ice and aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure to give(R)—N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(62.1 mg, 0.154 mmol, 97%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.27 (9H, d, J=0.8 Hz), 1.39 (3H, t, J=7.0Hz), 2.68-2.95 (2H, m), 3.12-3.21 (2H, m), 4.01 (2H, q, J=7.0 Hz), 4.72(1H, s), 5.13 (1H, brs), 6.64 (1H, d, J=2.6 Hz), 6.79 (1H, dd, J=8.7,2.6 Hz), 7.01 (1H, dd, J=10.6, 4.5 Hz), 7.49 (1H, d, J=8.7 Hz), 8.10(1H, dd, J=9.8, 6.0 Hz), 9.76 (1H, brs).

(Step 7)

Dihydro-2H-pyran-2,6(3H)-dione (27.1 mg, 0.24 mmol) was added to asolution of(R)—N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(64 mg, 0.16 mmol) and TEA (0.033 mL, 0.24 mmol) in THF (2.0 mL) at roomtemperature, and the mixture was stirred overnight at room temperature.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (Diol, solventgradient; 20→90% ethyl acetate/hexane), and crystallized from ethylacetate/hexane to give the title compound (45.7 mg, 0.088 mmol, 55.7%)as white crystals.

¹H NMR (300 MHz, DMSO-d): δ 0.26 (9H, s), 1.30 (3H, t, J=7.0 Hz),1.63-1.81 (2H, m), 2.17-2.33 (2H, m), 2.35-2.61 (2H, m), 2.68-2.86 (1H,m), 2.99-3.17 (1H, m), 3.43-3.59 (1H, m), 3.89-4.07 (3H, m), 5.93 (1H,s), 6.72-6.85 (2H, m), 7.21 (1H, dd, J=10.4, 4.7 Hz), 7.44-7.56 (1H, m),7.69 (1H, dd, J=10.4, 5.7 Hz), 10.30 (1H, s), 12.07 (1H, brs).

[α]_(D) ²⁵ −3.7 (c 0.2515, MeOH)

Example 1855-((1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)-1-methyl-H-pyrazole-3-carboxylicacid (Step 1)

HATU (117 mg, 0.31 mmol) was added to a solution ofN-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(100 mg, 0.26 mmol) (which can be synthesized in the same manner asabove), DIEA (0.088 mL, 0.51 mmol) and3-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (60.9 mg, 0.31mmol) in DMF (2.0 mL) at room temperature, and the mixture was stirredat room temperature for 2 hr. To the reaction mixture was added water,and the mixture was extracted with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent; ethyl acetate/hexane) to giveethyl5-(1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methyl-1H-pyrazole-3-carboxylate(90.8 mg, 0.159 mmol, 62.1%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.32 (9H, s), 1.37-1.45 (3H, m), 2.93-3.14(2H, m), 3.82 (3H, s), 3.83-3.89 (1H, m), 3.90-4.01 (1H, m), 4.07-4.17(4H, m), 4.36-4.48 (2H, m), 5.98 (1H, s), 6.72-6.92 (2H, m), 6.95-7.08(2H, m), 7.19 (1H, d, J=8.3 Hz), 9.01 (1H, s).

(Step 2)

1N Aqueous sodium hydroxide solution (0.308 mL, 0.31 mmol) was added toa solution of ethyl5-(1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methyl-1H-pyrazole-3-carboxylate(88 mg, 0.15 mmol) in a mixed solvent of EtOH (1.0 mL) and THF (1.0 mL)at room temperature, and the mixture was stirred overnight at roomtemperature. The reaction mixture was concentrated under reducedpressure, 1N hydrochloric acid was added thereto until the pH of themixture became 2 to 3, and the mixture was extracted with ethyl acetate.The organic layer was dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (Diol, solvent gradient; 20→90% ethylacetate/hexane), and then preparative HPLC (C18, mobile phase:water/acetonitrile (containing 0.1% TFA)) to give the title compound(6.2 mg, 0.011 mmol, 7.41%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 0.30 (9H, s), 2.76-2.94 (1H, m), 3.04-3.17(1H, m), 3.58-3.70 (1H, m), 3.74 (3H, s), 3.74-3.82 (1H, m), 3.90 (3H,s), 3.96-4.09 (1H, m), 5.68 (1H, s), 6.75-6.92 (2H, m), 7.02 (1H, s),7.23 (2H, d, J=9.4 Hz), 7.55 (1H, d, J=7.9 Hz), 10.89 (1H, s).

Example 186 ethylN-((1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)-beta-alaninate

TEA (0.056 mL, 0.40 mmol) was added to a solution of ethyl3-isocyanatopropionate (0.053 mL, 0.40 mmol) andN-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(130 mg, 0.33 mmol) in THF (2.0 mL), and the mixture was stirred at roomtemperature for 4 hr. To the reaction mixture was added water, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 10→50% ethylacetate/hexane) to give ethyl3-(1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxamide)propanoate(145.3 mg, 0.272 mmol, 82%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 0.29 (9H, s), 1.12-1.19 (3H, m), 2.37-2.55(2H, m), 2.67-2.84 (1H, m), 3.00-3.17 (1H, m), 3.22-3.41 (3H, m), 3.72(3H, s), 3.75-3.85 (1H, m), 3.99-4.08 (2H, m), 5.52 (1H, s), 6.71 (1H,t, J=5.5 Hz), 6.76-6.84 (2H, m), 7.15-7.26 (2H, m), 7.39-7.46 (1H, m),10.64 (1H, s).

Example 187(1R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-((2,4-dioxo-1,3-thiazolidin-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

HATU (58.4 mg, 0.15 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(50 mg, 0.13 mmol), DIEA (0.044 mL, 0.26 mmol) and2-(2,4-dioxothiazolidin-5-yl)acetic acid (26.9 mg, 0.15 mmol) in DMF(2.0 mL) at room temperature, and the mixture was stirred at roomtemperature for 2 hr. To the reaction mixture was added water, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 10→50% ethylacetate/hexane, 0→10% MeOH/ethyl acetate), and recrystallized from ethylacetate/hexane to give the title compound (36.3 mg, 0.066 mmol, 51.8%)as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 0.29 (9H, s), 2.76-2.90 (1H, m), 3.08-3.22(1H, m), 3.24-3.38 (2H, m), 3.39-3.58 (1H, m), 3.73 (3H, s), 3.94-4.09(1H, m), 4.54-4.70 (1H, m), 5.61 (1H, s), 6.77-6.90 (2H, m), 7.12-7.27(2H, m), 7.44 (1H, t, J=8.3 Hz), 10.77 (1H, d, J=11.7 Hz), 11.96 (1H,brs).

Example 188N-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)-beta-alanine(Step 1)

HATU (44.2 mg, 0.12 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(50 mg, 0.13 mmol), benzyl 3-(((4-nitrophenoxy)carbonyl)amino)propanoate (52.9 mg, 0.15 mmol) and DIEA (0.045 mL, 0.26mmol) in DMF (2.0 mL) at room temperature, and the mixture was stirredat room temperature for 3 hr. To the reaction mixture was added water,and the mixture was extracted with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 0→20% ethylacetate/hexane) to give crude benzyl(R)-3-(1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxamide)propanoate(39.2 mg, 0.066 mmol, 51.4%) as a colorless oil.

MS(API): Calculated 595.7. Found 594.3 (M−H).

(Step 2)

A solution of benzyl(R)-3-(1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxamide)propanoate(39 mg, 0.07 mmol) and 10% palladium-carbon (10 mg, 0.09 mmol, 50% wet)in MeOH (2.0 mL) was stirred under hydrogen atmosphere (1 atm) at roomtemperature for 2 hr. The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (solvent gradient;20→90% ethyl acetate/hexane) to give the title compound (12.0 mg, 0.024mmol, 25.3-) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 0.29 (9H, s), 2.32-2.47 (3H, m), 2.70-2.84(1H, m), 3.03-3.15 (1H, m), 3.19-3.41 (2H, m), 3.72 (3H, s), 3.75-3.85(1H, m), 5.52 (1H, s), 6.66-6.84 (3H, m), 7.22 (2H, d, J=9.8 Hz),7.38-7.47 (1H, m), 10.66 (1H, s), 12.26 (1H, s).

Example 1895-(2-((1R)-1-((4-tert-butyl-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1,2-oxazole-3-carboxylicacid (Step 1)

HATU (44.2 mg, 0.12 mmol) was added to a solution of(R)—N-(4-(tert-butyl)-3,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride (39.8 mg, 0.10 mmol), DIEA (0.041 mL, 0.23 mmol) and2-(3-(tert-butoxycarbonyl)isoxazol-5-yl)acetic acid (22 mg, 0.10 mmol)in DMF (4 mL)) at 0° C., and the mixture was stirred at 0° C. for 2 hr.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 5→90% ethyl acetate/hexane) to givecrude tert-butyl(R)-5-(2-(1-((4-(tert-butyl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)isoxazole-3-carboxylate as a pale yellow oil. The total amount thereofwas used for the next step.

MS(API): Calculated 583.6. Found 582.3 (M−H).

(Step 2)

Cooled TFA (4 mL) was added to the crude tert-butyl(R)-5-(2-(1-((4-(tert-butyl)-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)isoxazole-3-carboxylateat 0° C., and the mixture was stirred at 0° C. for 2 hr. The reactionmixture was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (Diol, solventgradient; 10→90% ethyl acetate/hexane, 0→20% MeOH/ethyl acetate) to givethe title compound (5.00 mg, 9.48 μmol) as a solid.

Example 1905-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(oxetan-3-yloxy)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

Dihydro-2H-pyran-2,6(3H)-dione (45.3 mg, 0.40 mmol) was added to asolution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-(oxetan-3-yloxy)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(132 mg, 0.31 mmol) (which can be synthesized in the same manner asabove) and TEA (0.055 mL, 0.40 mmol) in THF (2 mL) at room temperature,and the mixture was stirred overnight at room temperature. The reactionmixture was concentrated under reduced pressure, and the obtainedresidue was crystallized from THF and water. The crystals were collectedby filtration with water and hexane to give the title compound (127 mg,0.232 mmol, 76%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 0.29 (9H, s), 1.69-1.81 (2H, m), 2.20-2.31(2H, m), 2.35-2.60 (2H, m), 2.76-2.87 (1H, m), 3.04-3.19 (1H, m),3.42-3.56 (1H, m), 3.93-4.10 (1H, m), 4.44-4.58 (2H, m), 4.90 (2H, t,J=6.6 Hz), 5.17-5.33 (1H, m), 5.62 (1H, s), 6.58-6.77 (2H, m), 7.09-7.26(2H, m), 7.46 (1H, d, J=9.4 Hz), 10.78 (1H, s), 12.04 (1H, brs).

Example 1915-((1R)-6-(3,3-difluoroazetidin-1-yl)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

Dihydro-2H-pyran-2,6(3H)-dione (40.8 mg, 0.36 mmol) was added to asolution of(R)-6-(3,3-difluoroazetidin-1-yl)-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(118 mg, 0.27 mmol) (which can be synthesized in the same manner asabove) and TEA (0.050 mL, 0.36 mmol) in THF (2 mL) at room temperature,and the mixture was stirred overnight at room temperature. To thereaction mixture was added brine, and the mixture was extracted withethyl acetate. The organic layer was washed with water, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 30→100% ethyl acetate/hexane) to givethe title compound (51.0 mg, 0.094 mmol, 34.1%) as a white solid.

¹H NMR (300 MHz, DMSO-d): δ 1.28 (6H, d, J=1.5 Hz), 1.74 (2H, quin,J=7.3 Hz), 1.86 (2H, t, J=7.4 Hz), 2.20-2.32 (2H, m), 2.35-2.60 (2H, m),2.70-2.91 (3H, m), 3.04-3.18 (1H, m), 3.43-3.56 (1H, m), 3.96-4.08 (1H,m), 4.22 (4H, t, J=12.3 Hz), 5.61 (1H, s), 6.35-6.54 (2H, m), 7.15 (1H,s), 7.22 (1H, d, J=14.0 Hz), 7.42 (1H, d, J=9.1 Hz), 10.35 (1H, s),12.06 (1H, brs).

Example 192(1R)-2-(5-amino-5-oxopentanoyl)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

HATU (181 mg, 0.48 mmol) was added to a solution of5-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid (200 mg, 0.40 mmol), ammonium chloride (25.4 mg, 0.48 mmol) andDIEA (0.203 mL, 1.19 mmol) in DMF (4.0 mL) at room temperature, and themixture was stirred at room temperature for 3 hr. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→50% ethyl acetate/hexane), andrecrystallized from ethyl acetate/hexane to give the title compound(114.1 mg, 0.227 mmol, 57.2%) as white crystals.

¹H NMR (300 MHz, DMSO-d): δ 0.29 (9H, s), 1.73 (2H, quin, J=7.1 Hz),2.05-2.16 (2H, m), 2.32-2.57 (2H, m), 2.70-2.88 (1H, m), 3.04-3.18 (1H,m), 3.43-3.58 (1H, m), 3.73 (3H, s), 3.94-4.08 (1H, m), 5.62 (1H, s),6.71 (1H, brs), 6.77-6.87 (2H, m), 7.14-7.29 (3H, m), 7.46 (1H, d, J=9.4Hz), 10.76 (1H, s).

Example 1934-((1R)-6-(difluoromethoxy)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutanoicacid

Succinic anhydride (42.0 mg, 0.42 mmol) was added to a solution of(R)-6-(difluoromethoxy)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(132 mg, 0.32 mmol) and TEA (68 μL, 0.49 mmol) in THF (3.1 mL) at roomtemperature, and the mixture was stirred at room temperature for 15 hr.To the reaction mixture was added water, and 2N hydrochloric acid wasadded thereto until the pH of the mixture became 4. Then, the mixturewas extracted three times with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (Diol, solvent gradient; 30→100% ethylacetate/hexane) to give the title compound (120.5 mg, 0.237 mmol, 73.3%)as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.24 (9H, s), 2.68-2.96 (5H, m), 3.10-3.21(1H, m), 3.72 (1H, ddd, J=12.4, 7.5, 4.7 Hz), 3.86-3.95 (1H, m), 6.04(1H, s), 6.48 (1H, t), 6.97 (1H, s), 6.98-7.07 (2H, m), 7.16-7.25 (2H,m), 7.35 (1H, d, J=8.7 Hz), 9.17 (1H, s).

Example 1945-((1R)-6-(difluoromethoxy)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid (Step 1)

Sodium 2-chloro-2,2-difluoroacetate (4.36 g, 28.57 mmol) was added to asolution of 1-ethyl 2-tert-butyl6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (4.59 g, 14.28mmol) and cesium carbonate (6.98 g, 21.42 mmol) in DMF (70 mL) at roomtemperature, and the mixture was stirred at 95° C. for 3 hr. To thereaction mixture was added water, and the mixture was extracted threetimes with ethyl acetate. The organic layer was washed with brine, anddried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 4→20% ethyl acetate/hexane) to give1-ethyl 2-tert-butyl6-(difluoromethoxy)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (2.76g, 7.43 mmol, 52.0%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.21-1.29 (3H, m), 1.46-1.51 (9H, m),2.79-2.99 (2H, m), 3.67-3.89 (2H, m), 4.12-4.21 (2H, m), 5.38-5.57 (1H,m), 6.49 (1H, t), 6.92 (1H, s), 6.98 (1H, d, J=8.7 Hz), 7.46-7.53 (1H,m).

(Step 2)

2N Aqueous lithium hydroxide solution (22.21 mL, 44.43 mmol) was addedto a solution of 1-ethyl 2-tert-butyl6-(difluoromethoxy)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (2.75g, 7.40 mmol) in a mixed solvent of EtOH (11 mL) and THF (11 mL) at roomtemperature, and the mixture was stirred at room temperature for 2 hr.To the reaction mixture was added water, and 2N hydrochloric acid wasadded thereto until the pH of the mixture became 3. Then, the mixturewas extracted three times with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure to give2-(tert-butoxycarbonyl)-6-(difluoromethoxy)-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (2.48 g, 7.22 mmol, 98%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.40-1.53 (9H, m), 2.77-3.00 (2H, m),3.67-3.79 (2H, m), 5.39-5.60 (1H, m), 6.49 (1H, t), 6.93 (1H, d, J=2.3Hz), 6.99 (1H, dd, J=8.3, 2.3 Hz), 7.48 (1H, d, J=8.7 Hz).

(Step 3)

T3P (1.949 mL, 3.28 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-(difluoromethoxy)-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (750 mg, 2.18 mmol), 3-fluoro-4-(trimethylsilyl)aniline (400 mg,2.18 mmol), DIEA (1.903 mL, 10.92 mmol) and DMAP (294 mg, 2.40 mmol) inethyl acetate (16 mL), and the mixture was stirred at 65° C. for 16 hr.To the reaction mixture was added water, and the mixture was extractedthree times with ethyl acetate. The organic layer was washed with 10%aqueous citric acid solution, aqueous sodium hydrogen carbonate solutionand brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The precipitate was washed withcooled hexane to give tert-butyl6-(difluoromethoxy)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(933 mg, 1.834 mmol, 84%) as grayish white crystals.

¹H NMR (300 MHz, CDCl₃): δ 0.28 (9H, d, J=0.8 Hz), 1.53 (9H, s), 2.90(2H, t, J=5.7 Hz), 3.57 (1H, brs), 3.79 (1H, dt, J=12.6, 6.0 Hz), 5.65(1H, brs), 6.50 (1H, t), 6.97 (1H, s), 7.02 (1H, dd), 7.10 (1H, dd,J=7.9, 1.5 Hz), 7.25-7.31 (2H, m), 7.38 (1H, dd, J=10.4, 1.7 Hz), 9.03(1H, brs).

(Step 4)

tert-Butyl6-(difluoromethoxy)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.931 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-6-(difluoromethoxy)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.434 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-6-(difluoromethoxy)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.429 g, >99% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALPAK IA 50 mmID×500 mmL

solvent: hexane/EtOH=950/50

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 5)

Cooled TFA (5.5 mL) was added to tert-butyl(R)-6-(difluoromethoxy)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(429 mg, 0.84 mmol), and the mixture was stirred at room temperature for3 min. The reaction mixture was added to ice and aqueous sodium hydrogencarbonate solution, and potassium carbonate was added thereto until thepH of the mixture became 8. Then, the mixture was extracted three timeswith ethyl acetate. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The precipitate was washed with hexane to give(R)-6-(difluoromethoxy)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(341 mg, 0.835 mmol, 99%) as a colorless oil.

MS(API): Calculated 408.5. Found 409.2 (M+H).

(Step 6)

Dihydro-2H-pyran-2,6(3H)-dione (73.3 mg, 0.64 mmol) was added to asolution of(R)-6-(difluoromethoxy)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(202 mg, 0.49 mmol) and TEA (103 μL, 0.74 mmol) in THF (4.7 mL) at roomtemperature, and the mixture was stirred at room temperature for 4 hr.To the reaction mixture was added water, and 2N hydrochloric acid wasadded thereto until the pH of the mixture became 4. Then, the mixturewas extracted three times with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (Diol, solvent gradient; 30→100% ethylacetate/hexane) to give the title compound (190.5 mg, 0.365 mmol, 73.7%)as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.21 (9H, d, J=0.8 Hz), 2.10-2.20 (2H, m),2.37-2.63 (3H, m), 2.88-3.00 (2H, m), 3.30-3.41 (1H, m), 3.77 (1H, ddd,J=12.3, 8.5, 4.2 Hz), 4.06-4.16 (1H, m), 5.95 (1H, s), 6.48 (1H, t),6.84 (1H, dd, J=8.1, 1.7 Hz), 6.95-7.02 (2H, m), 7.04-7.12 (2H, m), 7.61(1H, d, J=8.3 Hz), 9.88 (1H, s), 11.26 (1H, brs).

Example 1954-((1R)-6-(difluoromethoxy)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutanoicacid (Step 1)

T3P (1.949 mL, 3.28 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-(difluoromethoxy)-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (750 mg, 2.18 mmol), 3,5-difluoro-4-(trimethylsilyl)aniline (440mg, 2.18 mmol), DIEA (1.903 mL, 10.92 mmol) and DMAP (294 mg, 2.40 mmol)in ethyl acetate (16 mL), and the mixture was stirred at 65° C. for 16hr. To the reaction mixture was added water, and the mixture wasextracted three times with ethyl acetate. The organic layer was washedwith 10% aqueous citric acid solution, aqueous sodium hydrogen carbonatesolution and brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The precipitate was washed withcooled hexane to give tert-butyl1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(difluoromethoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate(769 mg, 1.460 mmol, 66.8%) as grayish white crystals.

¹H NMR (300 MHz, CDCl₃): δ 0.32 (9H, t, J=1.3 Hz), 1.53 (9H, s),2.83-2.97 (2H, m), 3.59 (1H, brs), 3.72-3.81 (1H, m), 5.64 (1H, brs),6.50 (1H, t), 6.96-7.05 (4H, m), 7.26 (1H, s), 9.16 (1H, brs).

(Step 2)

tert-Butyl1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(difluoromethoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.75 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(difluoromethoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.363 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(difluoromethoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.352 g, >99% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALPAK IA 50 mmID×500 mmL

solvent: hexane/EtOH=950/50

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

Cooled TFA (4.5 mL) was added to tert-butyl(R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(difluoromethoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate(351 mg, 0.67 mmol), and the mixture was stirred at room temperature for3 min. The reaction mixture was added to ice and aqueous sodium hydrogencarbonate solution, and potassium carbonate was added thereto until thepH of the mixture became 8. Then, the mixture was extracted three timeswith ethyl acetate. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The precipitate was washed with hexane to give(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-(difluoromethoxy)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(294 mg, 0.689 mmol, quant.) as a colorless oil.

MS(API): Calculated 426.3. Found 427.31 (M+H).

(Step 4)

Succinic anhydride (42.1 mg, 0.42 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-(difluoromethoxy)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(138 mg, 0.32 mmol) and TEA (68 μL, 0.49 mmol) in THF (3.2 mL) at roomtemperature, and the mixture was stirred at room temperature for 15 hr.To the reaction mixture was added water, and 2N hydrochloric acid wasadded thereto until the pH of the mixture became 4. Then, the mixturewas extracted three times with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (Diol, solvent gradient; 30→100% ethylacetate/hexane) to give the title compound (134.3 mg, 0.255 mmol, 79%)as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.29 (9H, t), 2.67-2.76 (1H, m), 2.78-2.85(2H, m), 2.87-2.96 (2H, m), 3.11-3.22 (1H, m), 3.73 (1H, ddd, J=12.2,7.5, 4.9 Hz), 3.88-3.97 (1H, m), 6.03 (1H, s), 6.49 (1H, t), 6.89-6.96(2H, m), 6.96-7.03 (2H, m), 7.34 (1H, d, J=8.7 Hz), 9.26 (1H, s).

Example 1965-((1R)-6-(difluoromethoxy)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

Dihydro-2H-pyran-2,6(3H)-dione (52.5 mg, 0.46 mmol) was added to asolution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-(difluoromethoxy)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(151 mg, 0.35 mmol) and TEA (74 μL, 0.53 mmol) in THF (3.5 mL) at roomtemperature, and the mixture was stirred at room temperature for 4 hr.To the reaction mixture was added water, and 2N hydrochloric acid wasadded thereto until the pH of the mixture became 4. Then, the mixturewas extracted three times with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (Diol, solvent gradient; 30→100% ethylacetate/hexane) to give the title compound (141.7 mg, 0.262 mmol, 74.0%)as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.26 (9H, s), 2.11-2.25 (2H, m), 2.37-2.63(3H, m), 2.89-3.05 (2H, m), 3.34-3.45 (1H, m), 3.76 (1H, ddd, J=12.2,9.0, 3.8 Hz), 4.10-4.20 (1H, m), 5.86 (1H, s), 6.23-6.76 (3H, m), 6.97(1H, s), 7.00 (1H, dd), 7.64 (1H, d, J=8.7 Hz), 10.01 (1H, s), 11.47(1H, brs).

The compounds described in Examples 197 to 208 were synthesized by thereaction and purification in the same manner as in the above-mentionedExamples.

Example 1974-((1R)-6-(2,2-difluoroethoxy)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutanoicacid

¹H NMR (300 MHz, CDCl₃): δ 0.24 (9H, d, J=0.8 Hz), 2.64-2.93 (5H, m),3.13 (1H, ddd, J=15.7, 7.6, 4.7 Hz), 3.69 (1H, ddd, J=12.2, 7.6, 4.7Hz), 3.83-3.93 (1H, m), 4.11-4.22 (2H, m), 5.86-6.28 (2H, m), 6.76 (1H,d, J=2.3 Hz), 6.81 (1H, dd, J=8.7, 2.6 Hz), 7.06 (1H, dd, J=8.1, 1.7Hz), 7.20 (1H, dd, J=7.9, 6.4 Hz), 7.23-7.29 (2H, m), 9.09 (1H, s).

Example 1985-((1R)-6-(2,2-difluoroethoxy)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

¹H NMR (300 MHz, CDCl₃): δ 0.21 (9H, d, J=0.8 Hz), 2.09-2.19 (2H, m),2.38-2.63 (3H, m), 2.81-2.95 (2H, m), 3.25-3.36 (1H, m), 3.73 (1H, ddd,J=12.2, 8.6, 4.2 Hz), 4.01-4.22 (3H, m), 5.86-6.27 (2H, m), 6.74 (1H, d,J=2.3 Hz), 6.80 (1H, dd, J=8.3, 2.6 Hz), 6.88 (1H, dd, J=7.9, 1.9 Hz),7.05-7.16 (2H, m), 7.50 (1H, d, J=8.7 Hz), 9.77 (1H, s), 11.03 (1H,brs).

Example 1994-((1R)-6-(2,2-difluoroethoxy)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutanoicacid

¹H NMR (300 MHz, CDCl₃): δ 0.28 (9H, s), 2.67-2.96 (5H, m), 3.10-3.21(1H, m), 3.68 (1H, ddd, J=12.2, 7.8, 4.5 Hz), 3.88-3.97 (1H, m),4.10-4.22 (2H, m), 5.86-6.27 (2H, m), 6.76 (1H, d, J=2.3 Hz), 6.81 (1H,dd, J=8.3, 2.6 Hz), 6.88-6.96 (2H, m), 7.29 (1H, d, J=8.7 Hz), 9.28 (1H,s).

Example 2005-((1R)-6-(2,2-difluoroethoxy)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

¹H NMR (300 MHz, CDCl₃): δ 0.26 (9H, s), 2.10-2.20 (2H, m), 2.39-2.63(3H, m), 2.84-3.00 (2H, m), 3.30-3.42 (1H, m), 3.67-3.77 (1H, m),4.07-4.22 (3H, m), 5.83 (1H, s), 6.07 (1H, tt), 6.71-6.78 (3H, m), 6.81(1H, dd, J=8.3, 2.6 Hz), 7.54 (1H, d, J=8.7 Hz), 9.94 (1H, s), 11.27(1H, brs).

[α]_(D) ²⁵ −3.2 (c 0.2525, MeOH)

Example 2014-((1R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(2,2,2-trifluoroethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutanoicacid

¹H NMR (300 MHz, CDCl₃): δ 0.24 (9H, s), 2.67-2.93 (5H, m), 3.09-3.20(1H, m), 3.69 (1H, ddd, J=12.3, 7.6, 4.7 Hz), 3.85-3.94 (1H, m), 4.32(2H, q, J=8.3 Hz), 6.01 (1H, s), 6.79 (1H, d, J=2.3 Hz), 6.83 (1H, dd,J=8.7, 2.6 Hz), 7.05 (1H, dd, J=8.1, 1.7 Hz), 7.19 (1H, dd, J=7.9, 6.4Hz), 7.22-7.27 (1H, m), 7.30 (1H, d, J=8.7 Hz), 9.14 (1H, s).

Example 2025-((1R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(2,2,2-trifluoroethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

¹H NMR (300 MHz, CDCl₃): δ 0.21 (9H, s), 2.10-2.18 (2H, m), 2.38-2.63(3H, m), 2.82-2.96 (2H, m), 3.25-3.37 (1H, m), 3.74 (1H, ddd, J=12.2,8.4, 4.0 Hz), 4.02-4.12 (1H, m), 4.33 (2H, q, J=7.9 Hz), 5.93 (1H, s),6.78 (1H, d, J=2.6 Hz), 6.83 (1H, dd, J=8.7, 2.6 Hz), 6.87 (1H, dd,J=7.9, 1.9 Hz), 7.05-7.15 (2H, m), 7.52 (1H, d, J=8.7 Hz), 9.78 (1H, s),11.08 (1H, brs).

Example 2034-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(2,2,2-trifluoroethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutanoicacid

¹H NMR (300 MHz, CDCl₃): δ 0.29 (9H, s), 2.65-2.96 (5H, m), 3.08-3.19(1H, m), 3.70 (1H, ddd, J=12.3, 7.7, 4.9 Hz), 3.85-3.94 (1H, m), 4.33(2H, q, J=8.3 Hz), 6.00 (1H, s), 6.80 (1H, d, J=2.3 Hz), 6.84 (1H, dd),6.90-6.98 (2H, m), 7.28 (1H, d), 9.20 (1H, s).

Example 2045-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(2,2,2-trifluoroethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

¹H NMR (300 MHz, CDCl₃): δ 0.26 (9H, t, J=1.3 Hz), 2.10-2.24 (2H, m),2.37-2.63 (3H, m), 2.85-3.01 (2H, m), 3.30-3.43 (1H, m), 3.68-3.78 (1H,m), 4.07-4.16 (1H, m), 4.33 (2H, q, J=8.3 Hz), 5.84 (1H, s), 6.71-6.79(3H, m), 6.83 (1H, dd, J=8.7, 2.6 Hz), 7.56 (1H, d, J=8.7 Hz), 9.95 (1H,s), 11.32 (1H, brs).

Example 2054-((1R)-6-(difluoromethoxy)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutanoicacid

¹H NMR (300 MHz, CDCl₃): δ 1.30 (6H, s), 1.87 (2H, t, J=7.4 Hz),2.66-2.97 (7H, m), 3.06-3.17 (1H, m), 3.69-3.79 (1H, m), 3.81-3.91 (1H,m), 6.02 (1H, s), 6.49 (1H, t), 6.96-7.06 (4H, m), 7.28 (1H, d, J=8.3Hz), 8.88 (1H, s).

Example 2065-((1R)-6-(difluoromethoxy)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

¹H NMR (300 MHz, CDCl₃): δ 1.27 (6H, d, J=3.0 Hz), 1.83 (2H, t, J=7.4Hz), 2.07-2.16 (2H, m), 2.46 (2H, t), 2.58 (1H, dt, J=15.2, 7.3 Hz),2.68-2.85 (3H, m), 2.88-3.00 (1H, m), 3.19-3.31 (1H, m), 3.77 (1H, ddd,J=12.2, 7.6, 4.3 Hz), 4.01 (1H, ddd, J=12.1, 7.2, 4.5 Hz), 5.98 (1H, s),6.48 (1H, t), 6.86 (1H, s), 6.94-7.03 (3H, m), 7.50 (1H, d, J=8.3 Hz),9.53 (1H, s), 10.99 (1H, brs).

[α]_(D) ²⁵ +22.7 (c 0.2540, MeOH)

Example 2074-((1R)-6-(2,2-difluoroethoxy)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutanoicacid

¹H NMR (300 MHz, CDCl₃): δ 1.30 (6H, s), 1.86 (2H, t, J=7.2 Hz),2.65-2.93 (7H, m), 3.06-3.17 (1H, m), 3.70 (1H, ddd, J=12.4, 7.5, 4.7Hz), 3.81-3.91 (1H, m), 4.10-4.22 (2H, m), 5.87-6.28 (2H, m), 6.75 (1H,d, J=2.3 Hz), 6.81 (1H, dd, J=8.3, 2.6 Hz), 6.99-7.06 (2H, m), 7.23 (1H,d, J=8.7 Hz), 8.88 (1H, s).

Example 2085-((1R)-6-(2,2-difluoroethoxy)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

¹H NMR (300 MHz, CDCl₃): δ 1.27 (6H, d, J=2.3 Hz), 1.83 (2H, t, J=7.4Hz), 2.06-2.15 (2H, m), 2.47 (2H, t), 2.53-2.73 (2H, m), 2.78 (2H, t,J=7.6 Hz), 2.83-2.94 (1H, m), 3.16-3.27 (1H, m), 3.72 (1H, ddd, J=12.2,7.8, 4.5 Hz), 3.97 (1H, ddd, J=12.2, 7.1, 4.5 Hz), 4.11-4.22 (2H, m),5.86-6.27 (2H, m), 6.74 (1H, d, J=2.6 Hz), 6.80 (1H, dd, J=8.7, 2.6 Hz),6.89 (1H, s), 7.02 (1H, dd, J=12.1, 1.5 Hz), 7.40 (1H, d, J=8.3 Hz),9.43 (1H, s), 10.88 (1H, brs).

Example 209(4R)-5-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxy-5-oxopentanoicacid (Step 1)

A solution of sodium nitrite (539 mg, 7.81 mmol) in water (3 mL) wasadded to a solution of (R)-2-amino-5-(benzyloxy)-5-oxopentanoic acid(309 mg, 1.30 mmol) in conc. sulfuric acid (2 mL, 1.30 mmol) at 0° C.,and the mixture was stirred at 0° C. overnight. The reaction mixture wassaturated with sodium chloride, and the mixture was extracted with ethylacetate. The organic layer was dried over sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue wascrystallized from ethyl acetate to give(R)-2-hydroxy-5-(benzyloxy)-5-oxopentanoic acid.

MS(API): Calculated 238.2. Found 237.2 (M+H).

(Step 2)

HATU (43.4 mg, 0.11 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(42 mg, 0.10 mmol), (R)-2-hydroxy-5-(benzyloxy)-5-oxopentanoic acid(49.5 mg, 0.21 mmol) and DIEA (0.020 mL, 0.11 mmol) in DMF (4 mL) at 0°C., and the mixture was stirred at 0° C. for 2 hr. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 5→90% ethyl acetate/hexane) to givebenzyl(4R)-5-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxy-5-oxopentanoateas a white solid.

MS(API): Calculated 624.8. Found 625.5 (M+H).

(Step 3)

A solution of benzyl(4R)-5-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxy-5-oxopentanoateand 10% palladium-carbon in MeOH (4 mL) was stirred under hydrogenatmosphere (1 atm) at room temperature for 3 hr. The catalyst wasfiltered off, and the filtrate was concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(solvent gradient; 10→100% ethyl acetate/hexane) to give the titlecompound (7.00 mg, 0.013 mmol) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 0.30 (9H, s), 1.30 (3H, t, J=7.0 Hz),1.57-1.74 (1H, m), 1.81-1.97 (1H, m), 2.30-2.42 (2H, m), 2.74-2.88 (1H,m), 2.97-3.15 (1H, m), 3.67 (1H, ddd, J=12.3, 8.1, 3.8 Hz), 3.90-4.15(3H, m), 4.43 (1H, dd, J=8.3, 3.8 Hz), 5.62 (1H, s), 6.74-6.87 (2H, m),7.20 (2H, d, J=9.8 Hz), 7.39-7.49 (1H, m), 10.85 (1H, s).

Example 2106-((1R)-6-ethoxy-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-6-oxohexanoicacid

Oxepane-2,7-dione (50.1 mg, 0.39 mmol) was added to a solution of(R)-6-ethoxy-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(115 mg, 0.30 mmol) and TEA (0.054 mL, 0.39 mmol) in THF (2.0 mL) atroom temperature, and the mixture was stirred at room temperature for 5hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography (Diol,solvent gradient; 20→90% ethyl acetate/hexane) to give the titlecompound (35.0 mg, 0.069 mmol, 22.80-) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 1.22-1.33 (9H, m), 1.42-1.65 (4H, m),1.79-1.92 (2H, m), 2.10-2.30 (2H, m), 2.37-2.58 (2H, m), 2.69-2.90 (3H,m), 2.99-3.18 (1H, m), 3.45-3.62 (1H, m), 3.91-4.10 (3H, m), 5.64 (1H,s), 6.72-6.84 (2H, m), 7.10-7.28 (2H, m), 7.38-7.50 (1H, m), 10.40 (1H,s), 12.06 (1H, brs).

Example 2116-((1R)-6-ethoxy-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-6-oxohexanoicacid

Oxepane-2,7-dione (27.6 mg, 0.22 mmol) was added to a solution of(R)-6-ethoxy-N-(3-fluoro-4-(trimethylsilyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(64 mg, 0.17 mmol) and TEA (0.030 mL, 0.22 mmol) in THF (2.0 mL) at roomtemperature, and the mixture was stirred at room temperature for 5 hr.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (Diol, solventgradient; 20→90% ethyl acetate/hexane) to give the title compound (23.7mg, 0.046 mmol, 27.8-) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 0.24 (9H, s), 1.29 (3H, t, J=7.0 Hz),1.43-1.64 (4H, m), 2.09-2.30 (2H, m), 2.37-2.58 (2H, m), 2.68-2.87 (1H,m), 3.01-3.19 (1H, m), 3.45-3.59 (1H, m), 3.90-4.09 (3H, m), 5.60-5.69(1H, m), 6.72-6.84 (2H, m), 7.25-7.37 (2H, m), 7.45 (2H, d, J=11.0 Hz),10.60 (1H, s), 12.04 (1H, brs).

The compound described in Example 212 was synthesized by the reactionand purification in the same manner as in the above-mentioned Examples.

Example 2125-((5R)-2-(difluoromethoxy)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-oxopentanoicacid

¹H NMR (300 MHz, CDCl₃): δ 1.27 (6H, d, J=3.0 Hz), 1.83 (2H, t, J=7.4Hz), 2.01-2.20 (2H, m), 2.33-2.61 (3H, m), 2.68-2.95 (3H, m), 3.02-3.13(1H, m), 3.21 (1H, dt), 3.95-4.10 (2H, m), 5.99 (1H, s), 6.76-6.82 (2H,m), 6.97 (1H, dd, J=11.7, 1.5 Hz), 7.47 (1H, t), 7.87 (1H, d, J=8.3 Hz),9.61 (1H, s), 10.98 (1H, brs).

Example 213(1R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-((1,1-dioxido-4-oxo-1,2,5-thiadiazolysin-2-yl)acetyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(Step 1)

Chlorosulfonyl isocyanate (1.230 mL, 14.13 mmol) was added to a solutionof t-butyl alcohol (1.047 g, 14.13 mmol) in acetonitrile (20 mL) at 0°C., and the mixture was stirred at 0° C. for 1 hr. Then, pyridine (4 mL)was added thereto at 0° C., and the mixture was stirred at 0° C. for 40min (Reaction Mixture A). To a mixture of ethyl 2-aminoacetatehydrochloride in acetonitrile (10 mL) was added TEA (4.92 mL, 35.33mmol) at 0° C., and the mixture was stirred at 0° C. for 20 min. Thereaction mixture was filtered through Celite to remove the triethylaminehydrochloride, the filtrate was added to Reaction Mixture A at 0° C.,and the mixture was stirred overnight at room temperature. The reactionmixture was concentrated under reduced pressure, and the pH of theresidue was adjusted to 4 with 2N hydrochloric acid. Then, the residuewas extracted with ethyl acetate. The organic layer was dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was crystallized from ethylacetate/hexane to give ethyl2-((N-(tert-butoxycarbonyl)sulfamoyl)amino)acetate (3.58 g, 12.68 mmol,90%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 1.20 (3H, t, J=7.0 Hz), 1.42 (9H, s), 3.79(2H, d, J=6.0 Hz), 4.10 (2H, q, J=7.2 Hz), 8.06 (1H, brs), 10.89 (1H,s).

(Step 2)

DEAD (5.92 mL, 12.68 mmol) was added to a solution of ethyl2-((N-(tert-butoxycarbonyl)sulfamoyl)amino)acetate (3.58 g, 12.68 mmol),PPh₃ (3.33 g, 12.68 mmol) and benzyl alcohol (1.319 mL, 12.68 mmol) inTHF (20 mL) at 0° C., and the mixture was stirred overnight at roomtemperature. To the reaction mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 3→50% ethyl acetate/hexane) togive ethyl 2-((N-benzyl-N-(tert-butoxycarbonyl)sulfamoyl)amino)acetate(4.75 g, 12.75 mmol, 101%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.26 (3H, t, J=7.2 Hz), 1.52 (9H, s), 3.58(2H, d, J=4.9 Hz), 4.16 (2H, q, J=7.2 Hz), 4.83 (2H, s), 5.73 (1H, t,J=4.7 Hz), 7.28-7.41 (5H, m).

(Step 3)

4N Hydrogen chloride/ethyl acetate (15 mL) was added to a solution ofethyl 2-((N-benzyl-N-(tert-butoxycarbonyl)sulfamoyl)amino)acetate (4.75g, 12.75 mmol) in ethyl acetate (20 mL) at room temperature, and themixture was stirred at room temperature for 2 days. The reaction mixturewas concentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (solvent gradient; 10→60%ethyl acetate/hexane) to give ethyl 2-((N-benzyl sulfamoyl)amino)acetate(3.10 g, 11.38 mmol, 89%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 1.19 (3H, t, J=7.0 Hz), 3.65 (2H, s), 4.04(2H, brs), 4.10 (2H, q, J=7.2 Hz), 7.21-7.35 (5H, m), 7.39 (1H, brs),7.47 (1H, brs).

(Step 4)

Sodium methanolate (1.845 g, 34.15 mmol) was added to a solution ofethyl 2-((N-benzyl sulfamoyl)amino)acetate (3.1 g, 11.38 mmol) in MeOH(70 mL) at room temperature, and the mixture was stirred at roomtemperature for 20 hr. The reaction mixture was concentrated underreduced pressure, and to the obtained residue was added water. Theprecipitate was collected by filtration with water to give2-benzyl-1,2,5-thiadiazolysin-3-one 1,1-dioxide (1.370 g, 6.06 mmol,53.2%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 4.14 (2H, s), 4.68 (2H, s), 7.21-7.43 (5H,m), 8.57 (1H, brs).

(Step 5)

Sodium hydride (60% oil, 72.2 mg, 1.80 mmol) was added to a solution of2-benzyl-1,2,5-thiadiazolysin-3-one 1,1-dioxide (314 mg, 1.39 mmol) inacetonitrile (6 mL) at 0° C., and the mixture was stirred at the sametemperature for 30 min. tert-Butyl bromoacetate (0.291 mL, 1.80 mmol)was added thereto, and the mixture was stirred overnight at roomtemperature. To the reaction mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 3→50% ethyl acetate/hexane) togive tert-butyl2-(5-benzyl-1,1-dioxido-4-oxo-1,2,5-thiadiazolysin-2-yl)acetate (421 mg,1.237 mmol, 89%) as white crystals.

¹H NMR (300 MHz, CDCl₃): δ 1.43 (s, 9H) 3.91 (s, 2H) 4.20 (s, 2H) 4.77(s, 2H) 7.28-7.39 (m, 3H) 7.40-7.48 (m, 2H)

(Step 6)

Cooled TFA (5 mL) was added to tert-butyl2-(5-benzyl-1,1-dioxido-4-oxo-1,2,5-thiadiazolysin-2-yl)acetate (421 mg,1.24 mmol) at 0° C., and the mixture was stirred at 0° C. for 50 min.The reaction mixture was concentrated under reduced pressure, and theobtained precipitate was collected by filtration with ethylacetate/heptane to give2-(5-benzyl-1,1-dioxido-4-oxo-1,2,5-thiadiazolysin-2-yl)acetic acid (327mg, 1.150 mmol, 93%) as a grayish white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 4.11 (s, 2H) 4.38 (s, 2H) 4.73 (s, 2H)7.14-7.49 (m, 5H) 13.16 (brs, 1H)

(Step 7)

HATU (108 mg, 0.28 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(104 mg, 0.26 mmol), DIEA (0.049 mL, 0.28 mmol) and2-(5-benzyl-1,1-dioxido-4-oxo-1,2,5-thiadiazolysin-2-yl)acetic acid (80mg, 0.28 mmol) in DMF (2 mL) at room temperature, and the mixture wasstirred at room temperature for 2 hr. To the reaction mixture was addedaqueous sodium hydrogen carbonate solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 3→70% ethyl acetate/hexane) to give(R)-2-(2-(5-benzyl-1,1-dioxido-4-oxo-1,2,5-thiadiazolysin-2-yl)acetyl)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(110 mg, 0.164 mmol, 63.8%) as a white solid.

MS(API): Calculated 670.8. Found 669.3 (M−H).

(Step 8)

A solution of(R)-2-(2-(5-benzyl-1,1-dioxido-4-oxo-1,2,5-thiadiazolysin-2-yl)acetyl)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(100 mg, 0.15 mmol) and 10% palladium-carbon (15.86 mg, 0.15 mmol) inMeOH (2 mL) was stirred under hydrogen atmosphere (1 atm) at roomtemperature for 2 hr. The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (solvent gradient;10→100% ethyl acetate/hexane) to give the title compound (19.00 mg,0.033 mmol, 21.95%) as a white solid.

¹H NMR (300 MHz, DMSO-dr): δ 0.30 (9H, s), 1.30 (3H, t, J=6.8 Hz), 2.83(1H, d, J=15.1 Hz), 3.02-3.21 (1H, m), 3.43-3.55 (1H, m), 3.76-3.94 (2H,m), 3.94-4.11 (4H, m), 4.22 (1H, d, J=16.2 Hz), 5.60 (1H, s), 6.75-6.87(2H, m), 7.20 (2H, d, J=9.8 Hz), 7.43 (1H, d, J=9.1 Hz), 10.77 (1H, s).

The compounds described in Examples 214 to 219 were synthesized by thereaction and purification in the same manner as in the above-mentionedExamples.

Example 214(5R)-6-((1,1-dioxido-4-oxo-1,2,5-thiadiazolysin-2-yl)acetyl)-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide

¹H NMR (300 MHz, DMSO-d): δ 1.29 (6H, s), 1.81-1.93 (2H, m), 2.80-3.08(4H, m), 3.73-4.34 (10H, m), 5.73 (1H, s), 6.73 (1H, d, J=8.7 Hz),7.11-7.27 (2H, m), 7.77 (1H, d, J=8.3 Hz), 10.46 (1H, s).

Example 2155-((1R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(2,2,2-trifluoroethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

¹H NMR (300 MHz, CDCl₃): δ 1.27 (6H, d, J=2.3 Hz), 1.83 (2H, t, J=7.4Hz), 2.06-2.16 (2H, m), 2.47 (2H, t), 2.52-2.64 (1H, m), 2.67-2.82 (3H,m), 2.84-2.95 (1H, m), 3.16-3.28 (1H, m), 3.73 (1H, ddd, J=12.2, 7.6,4.3 Hz), 3.98 (1H, ddd, J=12.1, 7.2, 4.5 Hz), 4.33 (2H, q, J=7.9 Hz),5.96 (1H, s), 6.78 (1H, d, J=2.3 Hz), 6.82 (1H, dd, J=8.3, 2.6 Hz), 6.88(1H, s), 7.02 (1H, dd, J=11.7, 1.5 Hz), 7.42 (1H, d, J=8.3 Hz), 9.44(1H, s), 10.85 (1H, brs).

Example 216(4R)-4-amino-5-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

¹H NMR (300 MHz, DMSO-dr₆): δ 0.30 (9H, s), 1.26-1.35 (3H, m), 1.39-1.58(1H, m, J=14.7, 8.7 Hz), 1.69-1.87 (1H, m), 2.41 (2H, t, J=6.8 Hz),2.75-2.90 (1H, m, J=16.2 Hz), 3.00-3.13 (1H, m), 3.58-3.70 (1H, m), 3.85(1H, dd, J=9.1, 3.0 Hz), 3.94-4.14 (3H, m), 5.65 (1H, s), 6.73-6.86 (2H,m), 7.14-7.33 (2H, m), 7.45 (1H, d, J=9.4 Hz), 10.86 (1H, s).

Example 2175-((R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-isopropoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

¹H NMR (300 MHz, DMSO-d₆): δ 1.23 (6H, d, J=6.0 Hz), 1.28 (6H, d, J=1.5Hz), 1.74 (2H, quin, J=7.2 Hz), 1.81-1.93 (2H, m), 2.16-2.32 (2H, m),2.35-2.62 (2H, m), 2.67-2.92 (3H, m), 3.01-3.18 (1H, m), 3.45-3.60 (1H,m), 3.93-4.07 (1H, m), 4.49-4.66 (1H, m), 5.64 (1H, s), 6.71-6.83 (2H,m), 7.13-7.29 (2H, m), 7.37-7.49 (1H, m), 10.42 (1H, s), 12.08 (1H,brs).

Example 2185-((1R)-6-(cyclopropylmethoxy)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

¹H NMR (300 MHz, DMSO-d₆): δ 0.21-0.35 (2H, m), 0.47-0.61 (2H, m),1.18-1.24 (1H, m), 1.28 (6H, d, J=1.5 Hz), 1.63-1.79 (2H, m), 1.82-1.91(2H, m), 2.17-2.34 (2H, m), 2.35-2.61 (2H, m), 2.70-2.92 (3H, m),2.99-3.18 (1H, m), 3.45-3.58 (1H, m), 3.73-3.87 (2H, m), 3.96-4.07 (1H,m), 5.55-5.67 (1H, m), 6.73-6.84 (2H, m), 7.12-7.27 (2H, m), 7.40-7.48(1H, m), 10.35-10.52 (1H, m), 12.10 (1H, brs)

Example 2195-((1R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-propoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

¹H NMR (300 MHz, DMSO-d₆): δ 0.95 (3H, t, J=7.4 Hz), 1.28 (6H, d, J=1.5Hz), 1.62-1.79 (3H, m), 1.80-1.92 (2H, m), 2.16-2.32 (3H, m), 2.34-2.62(2H, m), 2.67-2.91 (3H, m), 3.03-3.18 (1H, m), 3.46-3.60 (1H, m),3.83-3.94 (2H, m), 3.96-4.08 (1H, m), 5.53-5.70 (1H, m), 6.74-6.86 (2H,m), 7.12-7.27 (2H, m), 7.40-7.49 (1H, m), 10.36-10.52 (1H, m), 12.11(1H, brs).

Example 220(3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)azetidin-1-yl)acetic acid

Cooled TFA (4 mL) was added to tert-butyl(R)-2-(3-(5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)azetidin-1-yl)acetate(321 mg, 0.57 mmol) (which can be synthesized in the same manner as inExample 230), and the mixture was stirred at room temperature for 45min. The reaction mixture was added to ice and aqueous sodium hydrogencarbonate solution, and potassium carbonate was added thereto until thepH of the mixture became 7. Then, the mixture was subjected to saltprecipitation with sodium chloride, and the mixture was extracted threetimes with a mixed solvent of ethyl acetate/THF (3:1). The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue wassolidified with IPE/hexane to give the title compound (135.1 mg, 0.265mmol, 46.7%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 1.29 (6H, s), 1.87 (2H, t, J=7.4 Hz),2.82-2.94 (3H, m), 3.02 (1H, dt), 3.36 (1H, brs), 3.57-3.67 (1H, m),3.83 (3H, s), 3.95 (1H, ddd, J=12.9, 8.2, 4.9 Hz), 4.08-4.25 (4H, m),4.30-4.42 (3H, m), 5.78 (1H, s), 6.75 (1H, d, J=8.3 Hz), 7.20 (1H, s),7.25 (1H, d, J=12.5 Hz), 7.88 (1H, d, J=8.7 Hz), 1.67 (1H, s)

Example 2215-((1R)-1-((3-cyano-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid (Step 1)

T3P (3.61 mL, 6.14 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (658 mg, 2.05 mmol), 5-amino-2-(trimethylsilyl)benzonitrile (429mg, 2.25 mmol), DIEA (1.838 mL, 10.24 mmol) and DMAP (275 mg, 2.25 mmol)in ethyl acetate (5 mL), and the mixture was stirred overnight at 70° C.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with water, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 3→50% ethyl acetate/hexane) to givetert-butyl1-((3-cyano-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(310 mg, 0.628 mmol, 30.7%) as a pale yellow solid.

MS(API): Calculated 493.7. Found 492.3 (M−H).

(Step 2)

tert-Butyl1-((3-cyano-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.31 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((3-cyano-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.073 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-1-((3-cyano-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.063 g, >99% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALCEL OD (NL001) 50 mmID×500 mmL

solvent: hexane/EtOH=950/50

flow rate: 80 mL/min

temperature: 30° C.

(Step 3)

Cooled TFA (5 mL) was added to tert-butyl(R)-1-((3-cyano-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(75 mg, 0.15 mmol) at 0° C., and the mixture was stirred at 0° C. for 1hr. The reaction mixture was added to cooled aqueous sodium hydrogencarbonate solution, and the mixture was extracted twice with ethylacetate. The organic layer was dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure to give(R)—N-(3-cyano-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(59.8 mg, 0.152 mmol, 100%).

MS(API): Calculated 393.6. Found 394.3 (M+H).

(Step 4)

Dihydro-2H-pyran-2,6(3H)-dione (34.7 mg, 0.30 mmol) was added to asolution of(R)—N-(3-cyano-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(59.8 mg, 0.15 mmol) and TEA (0.042 mL, 0.30 mmol) in THF (2 mL) at roomtemperature, and the mixture was stirred overnight at room temperature.To the reaction mixture was added brine, and the mixture was extractedwith ethyl acetate. The organic layer was dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 10→100% ethyl acetate/hexane), and crystallized with ethylacetate/heptane to give the title compound (28.0 mg, 0.055 mmol, 36.3%)as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 0.28-0.38 (9H, m), 1.26-1.33 (3H, m),1.67-1.83 (2H, m), 2.21-2.30 (2H, m), 2.37-2.61 (2H, m), 2.68-2.90 (1H,m), 3.03-3.19 (1H, m), 3.44-3.58 (1H, m), 3.93-4.09 (3H, m), 5.65 (1H,s), 6.72-6.86 (2H, m), 7.46 (1H, d, J=8.3 Hz), 7.60 (1H, d, J=8.3 Hz),7.77 (1H, dd, J=8.3, 1.9 Hz), 8.07 (1H, d, J=1.9 Hz), 10.76 (1H, s),12.07 (1H, brs).

Example 222(2E)-4-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobut-2-enoicacid

HATU (82 mg, 0.22 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(70 mg, 0.18 mmol), DIEA (0.061 mL, 0.36 mmol) and trans-2-butenedioicacid (208 mg, 1.79 mmol) in DMF (2.0 mL) at room temperature, and themixture was stirred at room temperature for 5 hr. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 20→900% ethyl acetate/hexane), andthen preparative HPLC (C18, mobile phase: water/acetonitrile (containing0.1% TFA)) to give the title compound (15.4 mg, 0.032 mmol, 17.58%) as awhite solid.

¹H NMR (300 MHz, DMSO-dr): δ 0.30 (9H, s), 2.78-2.93 (1H, m), 3.06-3.21(1H, m), 3.60-3.71 (1H, m), 3.73 (3H, s), 4.08-4.21 (1H, m), 5.63-5.79(1H, m), 6.51-6.62 (1H, m), 6.77-6.90 (2H, m), 7.13-7.25 (2H, m),7.39-7.57 (2H, m), 10.84 (1H, s), 13.07 (1H, brs).

The compounds described in Examples 223 to 224 were synthesized by thereaction and purification in the same manner as in the above-mentionedExamples.

Example 223(1R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(((3S)-1,1-dioxido-4-oxo-1,2,5-thiadiazolysin-3-yl)acetyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆): δ 0.29 (9H, s), 1.30 (3H, t, J=7.0 Hz),2.77-2.99 (3H, m), 3.06-3.19 (1H, m, J=9.4 Hz), 3.43-3.55 (1H, m),3.95-4.11 (3H, m), 4.34-4.44 (1H, m), 5.66 (1H, s), 6.71-6.89 (2H, m),7.20 (2H, d, J=9.8 Hz), 7.44 (1H, d, J=8.3 Hz), 7.87 (1H, brs), 10.82(1H, s).

Example 224(1R)-2-(((3S)-1,1-dioxido-4-oxo-1,2,5-thiadiazolysin-3-yl)acetyl)-6-ethoxy-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

¹H NMR (300 MHz, DMSO-d): δ 1.24-1.34 (9H, m), 1.80-1.90 (2H, m),2.77-2.92 (3H, m), 2.93-3.21 (3H, m), 3.42-3.59 (1H, m), 3.94-4.10 (3H,m), 4.44 (1H, dd, J=6.6, 3.6 Hz), 5.58-5.74 (1H, m), 6.75-6.85 (2H, m),7.13-7.18 (1H, m), 7.22 (1H, d, J=12.5 Hz), 7.36-7.51 (1H, m), 8.09 (1H,brs), 10.37-10.51 (1H, m).

Example 2253-((((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)oxy)propanoicacid (Step 1)

A solution of bis(trichloromethyl) carbonate (147 mg, 0.50 mmol) in THF(2 mL) was added to a solution of tert-butyl 3-hydroxypropanoate (0.133mL, 0.90 mmol) and pyridine (0.120 mL, 1.49 mmol) in THF (2 mL) at 0°C., and the mixture was stirred at room temperature for 30 min. Thereaction mixture was concentrated under reduced pressure, the obtainedresidue was dissolved in DMF (2 mL), and the solution was cooled to 0°C. A solution of(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(100 mg, 0.27 mmol) and DIEA (0.236 mL, 1.35 mmol) in DMF (2 mL) wasadded thereto, and the mixture was stirred at room temperature for 1 hr.To the reaction mixture was added aqueous sodium hydrogen carbonatesolution, and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 10→50%ethyl acetate/hexane, 0→10% MeOH/ethyl acetate) to give3-(tert-butoxy)-3-oxopropyl(R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(120.2 mg, 0.222 mmol, 82%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.34 (6H, s), 1.45 (9H, s), 1.91 (2H, t,J=7.4 Hz), 2.57-2.67 (2H, m), 2.81-3.05 (4H, m), 3.48 (1H, brs), 3.91(3H, s), 4.29-4.62 (3H, m), 5.36-5.78 (1H, m), 6.63 (1H, d, J=8.7 Hz),7.04-7.23 (2H, m), 7.48 (1H, d, J=8.7 Hz), 8.60 (1H, brs).

(Step 2)

Cooled TFA (2.0 mL) was added to 3-(tert-butoxy)-3-oxopropyl(R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(120 mg, 0.22 mmol), and the mixture was stirred at room temperature for1 hr. The reaction mixture was added to ice and aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent gradient; 20→90% ethyl acetate/hexane) to give the titlecompound (72.3 mg, 0.149 mmol, 67.2%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 1.29 (6H, s), 1.80-1.93 (2H, m), 2.52-2.67(2H, m), 2.72-3.05 (4H, m), 3.73-4.00 (5H, m), 4.15-4.31 (2H, m),5.40-5.56 (1H, m), 6.72 (1H, d, J=8.3 Hz), 7.12-7.33 (2H, m), 7.78 (1H,d, J=8.3 Hz), 10.40-10.61 (1H, m), 12.30 (1H, brs).

The compound described in Example 226 was synthesized by the reactionand purification in the same manner as in the above-mentioned Examples.

Example 2264-((((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)oxy)butanoicacid

¹H NMR (300 MHz, DMSO-d): δ 1.29 (6H, s), 1.70-1.92 (3H, m), 2.19-2.38(3H, m), 2.79-2.91 (3H, m), 2.93-3.07 (1H, m), 3.83 (3H, s), 3.86-4.12(4H, m), 5.49 (1H, d, J=10.6 Hz), 6.72 (1H, d, J=8.3 Hz), 7.10-7.29 (2H,m), 7.79 (1H, d, J=8.3 Hz), 10.52 (1H, d, J=5.7 Hz), 12.14 (1H, brs).

Example 227N-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)-beta-alanine(Step 1)

A solution of benzyl 3-aminopropanoate 4-methylbenzenesulfonate (5.0 g,14.23 mmol) and 4-nitrophenyl chloroformate (5.74 g, 28.46 mmol) in THF(300 mL) was heated under reflux overnight. The reaction mixture waspoured into water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solvent; ethylacetate/hexane) to give benzyl3-(((4-nitrophenoxy)carbonyl)amino)propanoate (1.45 g, 4.21 mmol, 29.6%)as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 2.69 (2H, t, J=5.9 Hz), 3.49-3.66 (2H, m),5.18 (2H, s), 5.73 (1H, brs), 7.27-7.33 (2H, m), 7.34-7.44 (5H, m),8.18-8.29 (2H, m).

(Step 2)

To a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(100 mg, 0.25 mmol) and benzyl3-(((4-nitrophenoxy)carbonyl)amino)propanoate (102 mg, 0.30 mmol) in DMF(2.0 mL) was added DIEA (0.086 mL, 0.49 mmol) at room temperature, andthe mixture was stirred at room temperature for 2 hr. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent; ethyl acetate/hexane) to give benzyl(R)-3-(1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxamide)propanoate(46.5 mg, 0.076 mmol, 30.9%.) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 0.31 (9H, s), 1.41 (3H, t, J=7.0 Hz), 2.65(2H, t, J=5.7 Hz), 2.70-2.81 (1H, m), 2.96-3.09 (1H, m), 3.10-3.22 (1H,m), 3.49 (1H, dt, J=9.7, 4.8 Hz), 3.61 (2H, q, J=5.8 Hz), 4.04 (2H, q,J=7.0 Hz), 5.13 (2H, s), 5.38 (1H, t, J=5.9 Hz), 5.72 (1H, s), 6.74-6.83(2H, m), 6.99-7.09 (2H, m), 7.13 (1H, d, J=8.3 Hz), 7.30-7.39 (5H, m),9.76 (1H, s).

(Step 3)

A solution of benzyl(R)-3-(1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxamide)propanoate(45 mg, 0.07 mmol) and 10% palladium-carbon (10 mg, 0.09 mmol, 50% wet)in MeOH (2.0 mL) was stirred under hydrogen atmosphere (1 atm) at roomtemperature for 5 hr. The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (solvent gradient;20→390% ethyl acetate/hexane) to give the title compound (14.0 mg, 0.027mmol, 36.5%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 0.29 (9H, s), 1.29 (3H, t, J=6.8 Hz), 2.40(2H, t, J=7.2 Hz), 2.70-2.83 (1H, m), 3.00-3.15 (1H, m), 3.19-3.36 (3H,m), 3.73-3.86 (1H, m), 3.99 (2H, q, J=6.8 Hz), 5.51 (1H, s), 6.65-6.82(3H, m), 7.22 (2H, d, J=9.8 Hz), 7.41 (1H, d, J=9.8 Hz), 10.68 (1H, s),12.15 (1H, brs).

Example 2281-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)pyrrolidine-3-carboxylicacid

The title compound was synthesized using(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamideand benzyl pyrrolidine-3-carboxylate, by the reaction and purificationin the same manner as in Step 1 of Example 225 and Step 3 of Example227.

Example 2295-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-4,5-dioxopentanoicacid

The title compound was synthesized using(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamideand 2-oxopentanedioic acid, by the reaction and purification in the samemanner as in Example 1.

Example 230 benzyl(1-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)azetidin-3-yl)acetate

A solution of benzyl 2-(azetidin-3-yl)acetate (50.7 mg, 0.25 mmol) andpyridine (0.055 mL, 0.68 mmol) in THF (1 mL) was added to a solution ofbis(trichloromethyl) carbonate (135 mg, 0.45 mmol) in THF (1 mL) at 5°C., and the mixture was stirred at room temperature for 30 min. Thereaction mixture was concentrated under reduced pressure, the obtainedresidue was dissolved in DMF (1 mL), and the solution was cooled to 5°C. A solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamideand DIEA (0.135 mL, 0.76 mmol) in DMF (1 mL) was added thereto at roomtemperature, and the mixture was stirred at room temperature for 1 hr.To the reaction mixture was added water, and 2N hydrochloric acid wasadded thereto until the pH of the mixture became 4. Then, the mixturewas extracted with ethyl acetate. The organic layer was aqueous ammoniumchloride solution and washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent gradient; 3→33% ethyl acetate/hexane) to give the titlecompound (58 mg, 0.091 mmol, 60.2%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.27-0.34 (9H, m), 1.40 (3H, t, J=7.0 Hz),2.68-2.76 (2H, m), 2.83-3.13 (3H, m), 3.41-3.56 (2H, m), 3.61-3.73 (1H,m), 3.87-3.95 (1H, m), 3.97-4.07 (2H, m), 4.08-4.17 (1H, m), 4.30-4.42(1H, m), 5.12 (2H, s), 5.58 (1H, s), 6.69-6.83 (2H, m), 7.04 (3H, d,J=9.4 Hz), 7.34 (5H, d, J=1.5 Hz), 10.02-10.12 (1H, m)

Example 231(1-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)azetidin-3-yl)aceticacid

A solution of benzyl(1-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)azetidin-3-yl)acetate(45 mg, 0.07 mmol) and 10% palladium-carbon (30 mg, 0.01 mmol, 50% wet)in MeOH (3 mL) was stirred under hydrogen atmosphere (1 atm) at roomtemperature for 1 hr. The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (Diol, solventgradient; 20→80% ethyl acetate/hexane/) to give the title compound (34mg, 0.062 mmol, 88%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.31 (9H, brs), 1.40 (3H, t, J=7.0 Hz),2.67-2.75 (2H, m), 2.83-3.09 (3H, m), 3.42-3.60 (2H, m), 3.66-3.75 (1H,m), 3.90-3.97 (1H, m), 3.98-4.21 (3H, m), 4.32-4.43 (1H, m), 5.58 (1H,s), 6.68-6.73 (1H, m), 6.76-6.84 (1H, m), 7.00-7.14 (3H, m), 9.91-10.01(1H, m).

[α]_(D) ²⁵ −14.2 (c 0.2510, MeOH)

Example 232 benzyl(1-(((1R)-6-ethoxy-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)azetidin-3-yl)acetate

The title compound was synthesized using(R)-6-ethoxy-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride, by the reaction and purification in the same manner as inExample 230.

¹H NMR (300 MHz, CDCl₃): δ 1.32 (6H, s), 1.40 (3H, t, J=7.0 Hz), 1.88(2H, t, J=7.4 Hz), 2.71 (2H, dd, J=7.7, 2.1 Hz), 2.78-2.89 (3H, m),2.91-3.08 (1H, m), 3.50 (2H, d, J=5.3 Hz), 3.67 (1H, s), 3.90 (1H, s),3.97-4.07 (2H, m), 4.07-4.17 (2H, m), 4.35 (1H, s), 5.12 (2H, s), 5.58(1H, s), 6.69 (1H, d, J=2.6 Hz), 6.75-6.82 (1H, m), 7.05-7.21 (3H, m),7.29-7.40 (5H, m), 9.70 (1H, s).

Example 233(1-(((1R)-6-ethoxy-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)azetidin-3-yl)aceticacid

The title compound was synthesized using benzyl(1-(((1R)-6-ethoxy-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinolin-2(H)-yl)carbonyl)azetidin-3-yl)acetate,by the reaction and purification in the same manner as in Example 231.

¹H NMR (300 MHz, CDCl₃): δ 1.29-1.35 (6H, m), 1.40 (3H, t, J=6.8 Hz),1.89 (2H, t, J=7.4 Hz), 2.70 (2H, d, J=8.3 Hz), 2.78-3.05 (5H, m),3.47-3.60 (2H, m), 3.70 (1H, d, J=2.6 Hz), 3.91 (1H, d, J=2.6 Hz),3.96-4.07 (2H, m), 4.07-4.20 (2H, m), 4.36 (1H, s), 5.58 (1H, s), 6.69(1H, d, J=2.3 Hz), 6.75-6.82 (1H, m), 7.05-7.20 (3H, m), 9.56 (1H, s).

Example 234(2Z)-4-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobut-2-enoicacid

The title compound was synthesized using maleic acid and(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide,by the reaction and purification in the same manner as in Example 1.

¹H NMR (300 MHz, DMSO-d): δ 0.30 (9H, s), 2.68-2.89 (1H, m), 2.92-3.08(1H, m), 3.40-3.52 (1H, m), 3.73 (3H, s), 3.85-4.05 (1H, m), 5.70 (1H,s), 6.07 (1H, d, J=12.1 Hz), 6.75-6.87 (3H, m), 7.20-7.31 (2H, m), 7.43(1H, d, J=8.3 Hz), 10.65-10.81 (1H, m), 12.82 (1H, brs).

Example 2355-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(methylsulfonyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid (Step 1)

Lithium hydroxide monohydrate (4.00 g, 95.40 mmol) was added to amixture of 1-ethyl 2-tert-butyl6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (5.11 g, 15.90mmol) in a mixed solvent of THF (20 mL), EtOH (20 mL) and water (20 mL)at room temperature, and the mixture was stirred overnight at roomtemperature. The reaction mixture was concentrated under reducedpressure, and to the residue was added 6N hydrochloric acid. The mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure to give2-(tert-butoxycarbonyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (4.8 g, 16.36 mmol, 103%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 1.33-1.52 (9H, m), 2.61-2.87 (2H, m),3.41-3.68 (2H, m), 5.05-5.28 (1H, m), 6.45-6.75 (2H, m), 7.24 (1H, d,J=8.3 Hz), 9.41 (1H, d, J=4.2 Hz), 12.67 (1H, brs).

(Step 2)

A mixture of2-(tert-butoxycarbonyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (3.35 g, 11.42 mmol), benzyl bromide (6.79 mL, 57.11 mmol) andsodium hydrogen carbonate (1.919 g, 22.84 mmol) in DMF (50 mL) wasstirred at room temperature for 2 days. The reaction mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 2→50% ethyl acetate/hexane) to give2-tert-butyl 1-benzyl6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (3.91 g, 10.20mmol, 89%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.32-1.54 (9H, m), 2.57-3.03 (2H, m),3.50-3.84 (2H, m), 4.94-5.22 (3H, m), 5.30-5.65 (1H, m), 6.54-6.77 (2H,m), 7.18-7.47 (6H, m).

(Step 3)

1,1,1-Trifluoro-N-phenyl-N-(trifluoromethyl)sulfonylmethanesulfonamide(5.46 g, 15.30 mmol) was added to a solution of 2-tert-butyl 1-benzyl6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (3.91 g, 10.20mmol), DIEA (3.56 mL, 20.39 mmol) and DMAP (0.374 g, 3.06 mmol) in THF(30 mL) at room temperature, and the mixture was stirred at roomtemperature for 3 hr. The reaction mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 3→50% ethyl acetate/hexane), and thensilica gel column chromatography (NH, solvent gradient; 3→50% ethylacetate/hexane) to give 2-tert-butyl 1-benzyl6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate(4.35 g, 8.44 mmol, 83%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.35-1.52 (9H, m), 2.71-3.06 (2H, m),3.63-3.76 (1H, m), 3.77-3.98 (1H, m), 5.04-5.29 (2H, m), 5.44-5.75 (1H,m), 7.01-7.15 (2H, m), 7.19-7.40 (5H, m), 7.57 (1H, d, J=8.3 Hz).

(Step 4)

A solution of 2-tert-butyl 1-benzyl6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate(1.75 g, 3.39 mmol), bis(pinacolato)diboron (1.293 g, 5.09 mmol),PdCl₂(dppf) (0.248 g, 0.34 mmol) and potassium acetate (1.000 g, 10.18mmol) in DME (3 mL) was stirred under nitrogen gas atmosphere at 80° C.for 3 hr. To the reaction mixture was added ethyl acetate. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 3→50%ethyl acetate/hexane) to give 2-tert-butyl 1-benzyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate(1.810 g, 3.67 mmol, 108%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.34 (12H, s), 1.36-1.50 (9H, m), 2.76-3.04(2H, m), 3.64-3.86 (2H, m), 5.01-5.21 (2H, m), 5.42-5.70 (1H, m),7.26-7.36 (5H, m), 7.45-7.53 (1H, m), 7.57-7.68 (2H, m).

(Step 5)

Sodium periodate (2.354 g, 11.01 mmol) was added to a mixture of2-tert-butyl 1-benzyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate(1.81 g, 3.67 mmol) in a mixed solvent of water (2.500 mL) and acetone(10 mL) at room temperature, and the mixture was stirred at roomtemperature for 1 hr. To the reaction mixture was added 2N hydrochloricacid (3.67 mL) at room temperature, and the mixture was stirred at roomtemperature for additional 4 hr. To the reaction mixture was addedwater, and the precipitate was collected by filtration with water togive(1-((benzyloxy)carbonyl)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)boronicacid (1.100 g, 2.67 mmol, 72.9%) as a white solid.

MS(API): Calculated 411.3. Found 312.1 (M-Boc+H).

(Step 6)

(1-((Benzyloxy)carbonyl)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)boronicacid (1 g, 2.43 mmol), copper(II) acetate (0.022 g, 0.12 mmol), sodiummethanesulfinate (0.248 g, 2.43 mmol) and 1-butyl-3-methylimidazoliumtrifluoromethylsulfonate (1.5 mL, 6.74 mmol) were stirred overnight atroom temperature, and then overnight at 60° C. To the reaction mixturewas added water, and the mixture was extracted with ethyl acetate. Theorganic layer was dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 5→70% ethylacetate/hexane) to give crude 2-tert-butyl 1-benzyl6-(methylsulfonyl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (0.317g, 0.712 mmol, 29.3%) as a colorless oil.

(Step 7)

A solution of 2-tert-butyl 1-benzyl6-(methylsulfonyl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (317mg, 0.71 mmol) and 10% palladium-carbon (76 mg, 0.71 mmol, 50% wet) inMeOH (5 mL) was stirred under hydrogen atmosphere (1 atm) at roomtemperature for 2 days. The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure to give2-(tert-butoxycarbonyl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (253 mg, 0.712 mmol, 100%) as a colorless oil.

MS(API): Calculated 355.4. Found 709.3 (2M−H).

(Step 8)

T3P (1.256 mL, 2.14 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (253 mg, 0.71 mmol), 3,5-difluoro-4-(trimethylsilyl)aniline (143mg, 0.71 mmol), DIEA (0.622 mL, 3.56 mmol) and DMAP (87 mg, 0.71 mmol)in ethyl acetate (10 mL), and the mixture was stirred at 70° C. for 24hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 2→40% ethyl acetate/hexane), and thensilica gel column chromatography (NH, solvent gradient; 5→40% ethylacetate/hexane) to give tert-butyl1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(methylsulfonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(140 mg, 0.260 mmol, 36.5%) as a white solid.

MS(API): Calculated 538.7. Found 537.3 (M−H).

(Step 9)

tert-Butyl1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(methylsulfonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(140 mg) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(methylsulfonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(43.4 mg, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(methylsulfonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(45.2 mg, >99% ee).

purification condition by chiral column chromatography

column: CHIRALCEL OD (NL001) 50 mmID×500 mmL

solvent: hexane/EtOH=800/200

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 10)

Cooled TFA (5 mL) was added to tert-butyl(R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(methylsulfonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(43 mg, 0.08 mmol) under ice water, and the mixture was stirred underice water for 1 hr. The reaction mixture was added to ice and aqueoussodium hydrogen carbonate solution, and the mixture was extracted twicewith ethyl acetate. The organic layer was washed with brine, and driedover sodium sulfate, and the solvent was evaporated under reducedpressure to give(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(35.0 mg, 0.080 mmol, 100%).

MS(API): Calculated 438.6. Found 439.3 (M+H).

(Step 11)

Dihydro-2H-pyran-2,6(3H)-dione (11.84 mg, 0.10 mmol) was added to asolution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(35 mg, 0.08 mmol) and DIEA (18 μL, 0.10 mmol) in THF (2 mL) at roomtemperature, and the mixture was stirred overnight at room temperature.The reaction mixture was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(solvent gradient; 10→90% ethyl acetate/hexane), crystallized from ethylacetate/heptane to give the title compound (10.00 mg, 0.018 mmol,22.67%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 0.30 (9H, s), 1.67-1.84 (2H, m), 2.22-2.32(2H, m), 2.38-2.63 (2H, m), 2.93-3.08 (1H, m), 3.12-3.28 (4H, m),3.54-3.70 (1H, m), 3.96-4.15 (1H, m), 5.72-5.91 (1H, m), 7.21 (2H, d,J=9.4 Hz), 7.71-7.91 (3H, m), 10.95 (1H, s), 12.06 (1H, brs).

Example 2365-((1R)-6-ethoxy-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxy-3-methyl-5-oxopentanoicacid

The title compound was synthesized using(R)-6-ethoxy-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride and 3-methyl-3-hydroxyglutaric acid, by the reaction andpurification in the same manner as in Example 1.

Example 237 tert-butyl(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate

The title compound was synthesized using(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide,by the reaction and purification in the same manner as in Step 1 ofExample 213.

¹H NMR (300 MHz, CDCl₃): δ 0.25-0.37 (9H, m), 1.40 (3H, t, J=7.0 Hz),1.50 (9H, s), 2.77 (1H, dt, J=16.4, 4.6 Hz), 3.09-3.26 (1H, m),3.41-3.57 (1H, m), 3.75-3.88 (1H, m), 4.02 (2H, q, J=7.2 Hz), 5.59 (1H,s), 6.67 (1H, d, J=2.3 Hz), 6.84 (1H, dd, J=8.7, 2.6 Hz), 7.22 (2H, d,J=9.4 Hz), 7.28 (1H, s), 9.43 (1H, s) (The peak derived from NH was notobserved).

Example 2384-(((((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)amino)butanoicacid (Step 1)

A solution of benzyl 4-aminobutanoate 4-methylbenzenesulfonate (3.0 g,8.21 mmol) and 4-nitrophenyl chloroformate (3.31 g, 16.42 mmol) in THF(150 mL) was heated under reflux overnight. To the reaction mixture wasadded water, and the mixture was extracted with ethyl acetate. Theorganic layer was dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent; ethyl acetate/hexane) to givebenzyl 4-(((4-nitrophenoxy)carbonyl)amino)butanoate (1.59 g, 4.44 mmol,54.0%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.96 (2H, quin, J=7.0 Hz), 2.49 (2H, t, J=7.0Hz), 3.35 (2H, q, J=7.0 Hz), 5.14 (2H, s), 5.35 (1H, brs), 7.27-7.32(2H, m), 7.33-7.40 (5H, m), 8.1-8.27 (2H, m).

(Step 2)

DIEA (0.086 mL, 0.49 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(100 mg, 0.25 mmol) and benzyl 4-(((4-nitrophenoxy)carbonyl)amino)butanoate (97 mg, 0.27 mmol) in DMF (2.0 mL) at roomtemperature, and the mixture was stirred at room temperature for 5 hr.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent; ethyl acetate/hexane) to give benzyl(R)-4-(1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxamide)butanoate(41.3 mg, 0.066 mmol, 26.8%) as a colorless oil.

MS(API): Calculated 623.8. Found 622.3 (M−H).

(Step 3)

A solution of benzyl(R)-4-(1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxamide)butanoate(40 mg, 0.06 mmol) and 10% palladium-carbon (10 mg, 0.09 mmol, 50% wet)in MeOH (2.0 mL) was stirred under hydrogen atmosphere (1 atm) at roomtemperature for 2 hr. The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (solvent gradient;20→90% ethyl acetate/hexane) to give the title compound (22.3 mg, 0.042mmol, 65.2%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.29 (9H, s), 1.33-1.44 (3H, m), 1.77-1.99(2H, m), 2.37-2.49 (2H, m), 2.70-2.85 (1H, m), 3.06-3.49 (5H, m),3.60-3.72 (1H, m), 4.01 (2H, q, J=7.1 Hz), 5.18 (1H, brs), 5.75 (1H, s),6.68-6.81 (2H, m), 7.01 (2H, d, J=9.1 Hz), 7.18-7.31 (1H, m), 9.70 (1H,brs).

Example 2394-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)morpholine-2-carboxylicacid

The title compound was synthesized using benzyl morpholine-2-carboxylatehydrochloride and(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide,by the reaction and purification in the same manner as in Step 1 ofExample 225 and Step 3 of Example 227.

¹H NMR (300 MHz, CDCl₃): δ 0.31 (9H, d, J=5.3 Hz), 1.37-1.45 (3H, m),2.80-3.28 (3H, m), 3.30-4.35 (10H, m), 5.29-5.51 (1H, m), 6.64-6.85 (2H,m), 6.90-7.19 (3H, m), 9.74-10.08 (1H, m).

Example 2405-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxy-3-methyl-5-oxopentanoicacid

HATU (113 mg, 0.30 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(100 mg, 0.25 mmol), DIEA (0.127 mL, 0.74 mmol) and3-methyl-3-hydroxyglutaric acid (200 mg, 1.24 mmol) in DMF (2.0 mL) atroom temperature, and the mixture was stirred overnight at roomtemperature. To the reaction mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 20→90% ethyl acetate/hexane) togive the title compound (62.3 mg, 0.114 mmol, 45.9%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 0.29 (9H, s), 1.23-1.37 (6H, m), 2.64-2.87(3H, m), 2.89-3.01 (2H, m), 3.02-3.21 (1H, m), 3.48-3.63 (1H, m),3.93-4.16 (3H, m), 5.50 (1H, s), 5.65 (1H, s), 6.74-6.86 (2H, m),7.13-7.26 (2H, m), 7.38-7.50 (1H, m), 10.71 (1H, s), 12.07 (1H, brs).

Example 2415-((1R)-6-ethoxy-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinolin-2(H)-yl)-2,2-dimethyl-5-oxopentanoicacid

The title compound was synthesized using(R)-6-ethoxy-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride and 2,2-dimethylglutaric anhydride, by the reaction andpurification in the same manner as in Example 109.

¹H NMR (300 MHz, CDCl₃): δ 1.18-1.29 (12H, m), 1.39 (3H, t, J=7.0 Hz),1.82 (2H, t, J=7.4 Hz), 1.98-2.05 (2H, m), 2.55 (1H, dt, J=15.0, 7.4Hz), 2.65-2.94 (4H, m), 3.18-3.32 (1H, m), 3.65-3.79 (1H, m), 3.94-4.07(3H, m), 5.89 (1H, s), 6.66-6.77 (2H, m), 6.82 (1H, s), 6.90-7.03 (1H,m), 7.41 (1H, d, J=8.3 Hz), 9.52 (1H, s).

Example 2424-((((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)amino)butanoicacid (Step 1)

DIEA (0.107 mL, 0.61 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(120 mg, 0.31 mmol) and benzyl4-(((4-nitrophenoxy)carbonyl)amino)butanoate (121 mg, 0.34 mmol) in DMF(3.0 mL) at room temperature, and the mixture was stirred at roomtemperature for 3 hr. To the reaction mixture was added water, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent; ethyl acetate/hexane) to givebenzyl(R)-4-(1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxamide)butanoate(105.2 mg, 0.173 mmol, 56.1%) as a colorless oil.

MS(API): Calculated 609.7. Found 608.3 (M−H).

(Step 2)

A solution of benzyl(R)-4-(1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxamide)butanoate(100 mg, 0.16 mmol) and 10% palladium-carbon (20 mg, 0.19 mmol, 50% wet)in MeOH (2.0 mL) was stirred under hydrogen atmosphere (1 atm) at roomtemperature for 3 hr. The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (solvent gradient;20→390% ethyl acetate/hexane) to give the title compound (50.0 mg, 0.096mmol, 58.7%) as a white solid.

¹H NMR (300 MHz, DMSO-dr): δ 0.29 (9H, s), 1.56-1.74 (2H, m), 2.16-2.28(2H, m), 2.70-2.85 (1H, m), 2.99-3.16 (3H, m), 3.34-3.44 (1H, m), 3.72(3H, s), 3.77-3.88 (1H, m), 5.51 (1H, s), 6.67 (1H, t, J=5.3 Hz),6.76-6.83 (2H, m), 7.22 (2H, d, J=9.8 Hz), 7.43 (1H, d, J=9.8 Hz), 10.64(1H, s), 12.02 (1H, brs).

Example 2434-((((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)amino)butanoicacid (Step 1)

DEAD (0.080 mL, 0.17 mmol) was added to a solution oftert-butyl(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate(50 mg, 0.09 mmol) and PPh₃ (44.9 mg, 0.17 mmol) in THF (20 mL) at 0°C., and the mixture was stirred overnight at room temperature. Thereaction mixture was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(solvent gradient; 10→60% ethyl acetate/hexane) to give tert-butyl(R)-4-(N-(tert-butoxycarbonyl)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-2-sulfonamido)butanoate(63.0 mg, 0.087 mmol, 101%) as a colorless oil.

MS(API): Calculated 725.9. Found 724.4 (M−H).

(Step 2)

Cooled TFA (2 mL) was added to tert-butyl(R)-4-(N-(tert-butoxycarbonyl)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-2-sulfonamido)butanoate(63 mg, 0.09 mmol) under ice water, and the mixture was stirred at thesame temperature for 1 hr. Cooled TFA (2 mL) was added again thereto,and the mixture was stirred at the same temperature for 1 hr. Thereaction mixture was added to ice and aqueous sodium hydrogen carbonatesolution, and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified twice by silica gel column chromatography (solvent; 5% ethylacetate/hexane) to give the title compound (2.0 mg, 3.51 μmol, 4.05%) asa colorless oil.

MS(API): Calculated 569.7. Found 570.4 (M+H).

Example 244N-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)-2-methylalanine

The title compound was synthesized using benzyl2-amino-2-methylpropanoate and(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide,by the reaction and purification in the same manner as in Step 1 ofExample 225 and Step 3 of Example 227.

¹H NMR (300 MHz, CDCl₃): δ 0.30 (9H, t, J=1.3 Hz), 1.60 (6H, d, J=14.0Hz), 2.82-2.97 (1H, m), 2.97-3.13 (1H, m), 3.40-3.56 (1H, m), 3.81 (4H,s), 5.22-5.36 (1H, m), 5.59-5.74 (1H, m), 6.75 (1H, d, J=2.3 Hz),6.78-6.85 (1H, m), 7.12 (2H, d, J=9.5 Hz), 7.20 (1H, s), 9.07-9.29 (1H,m).

Example 245 benzylN-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)-D-alaninate

The title compound was synthesized using benzyl (R)-2-aminopropanoateand(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide,by the reaction and purification in the same manner as in Step 1 ofExample 225.

¹H NMR (300 MHz, CDCl₃): δ 0.29 (9H, t, J=1.3 Hz), 1.50 (3H, d, J=7.2Hz), 2.77-2.90 (1H, m), 3.11-3.28 (1H, m), 3.34-3.49 (1H, m), 3.78 (4H,s), 4.63 (1H, s), 5.10-5.29 (2H, m), 5.33-5.41 (1H, m), 5.70 (1H, s),6.72-6.82 (2H, m), 6.96 (2H, d, J=9.1 Hz), 7.21 (1H, d, J=8.3 Hz), 7.32(5H, s), 9.65-9.90 (1H, m).

Example 246N-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)-D-alanine

The title compound was synthesized using benzylN-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)-D-alaninate,by the reaction and purification in the same manner as in Step 3 ofExample 227.

¹H NMR (300 MHz, CDCl₃): δ 0.28 (9H, s), 1.48 (3H, d, J=7.2 Hz),2.72-2.90 (1H, m), 3.30 (2H, s), 3.78 (4H, s), 4.46-4.62 (1H, m),5.21-5.38 (1H, m), 5.68 (1H, s), 6.72 (2H, d, J=2.3 Hz), 6.91 (2H, d,J=9.1 Hz), 7.28 (1H, d, J=8.7 Hz), 9.41-9.58 (1H, m).

Example 2475-((1R)-6-cyano-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid (Step 1)

A solution of 1-ethyl 2-tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (2.5 g, 5.51mmol), Pd(PPh₃)₄ (0.191 g, 0.17 mmol) and zinc cyanide (0.712 g, 6.06mmol) in DMF (14 mL) was stirred overnight at 100° C. To the reactionmixture was added ethyl acetate. The mixture was washed with water andbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 3→60% ethyl acetate/hexane) togive 1-ethyl 2-tert-butyl6-cyano-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (0.400 g, 1.211mmol, 21.96%) as a colorless oil.

MS(API): Calculated 330.4. Found 329.1 (M−H).

(Step 2)

Lithium hydroxide monohydrate (152 mg, 3.63 mmol) was added to a mixtureof 1-ethyl 2-tert-butyl6-cyano-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (400 mg, 1.21mmol) in a mixed solvent of EtOH (10 mL) and water (10 mL) at roomtemperature, and the mixture was stirred overnight at room temperature.To the reaction mixture was added 2N hydrochloric acid, and the mixturewas extracted with ethyl acetate. The organic layer was dried overmagnesium sulfate, and the solvent was evaporated under reduced pressureto give2-(tert-butoxycarbonyl)-6-cyano-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (400 mg, 1.323 mmol, 109%) as a colorless oil.

MS(API): Calculated 302.3. Found 603(2M−H).

(Step 3)

T3P (2.335 mL, 3.97 mmol) was added to a solution of2-(tert-butoxycarbonyl)-6-cyano-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (400 mg, 1.32 mmol), 3,5-difluoro-4-(trimethylsilyl)aniline (266mg, 1.32 mmol), DIEA (1.155 mL, 6.62 mmol) and DMAP (162 mg, 1.32 mmol)in ethyl acetate (10 mL), and the mixture was stirred at 70° C. for 24hr. To the reaction mixture was added ethyl acetate. The mixture waswashed with water and brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 2→40%ethyl acetate/hexane), and then silica gel column chromatography (NH,solvent gradient; 5→40% ethyl acetate/hexane) to give tert-butyl6-cyano-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(290 mg, 0.597 mmol, 45.1%) as a white solid.

MS(API): Calculated 485.6. Found 484.2 (M−H).

(Step 4)

tert-Butyl6-cyano-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(290 mg) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-6-cyano-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(126 mg, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-6-cyano-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(135 mg, >99% ee).

purification condition by chiral column chromatography

column: CHIRALPAK AD (NF001) 50 mmID×500 mmL

solvent: hexane/EtOH=800/200

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 5)

Cooled TFA (5 mL) was added to tert-butyl(R)-6-cyano-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(125 mg, 0.26 mmol), and the mixture was stirred under ice water for 1.5hr. The reaction mixture was added to ice and aqueous sodium hydrogencarbonate solution, and the mixture was extracted twice with ethylacetate. The organic layer was washed with brine, and dried over sodiumsulfate, and the solvent was evaporated under reduced pressure to give(R)-6-cyano-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(99 mg, 0.257 mmol, 100%) as a white solid.

MS(API): Calculated 385.5. Found 386.2 (M+H).

(Step 6)

The title compound was synthesized using(R)-6-cyano-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide,by the reaction and purification in the same manner as in Example 82.

¹H NMR (300 MHz, DMSO-d₆): δ 0.30 (9H, s), 1.64-1.83 (2H, m), 2.19-2.30(2H, m), 2.38-2.61 (2H, m), 2.85-3.01 (1H, m), 3.07-3.22 (1H, m),3.51-3.70 (1H, m), 3.98-4.10 (1H, m), 5.80 (1H, s), 7.20 (2H, d, J=9.8Hz), 7.68-7.76 (2H, m), 7.79 (1H, s), 10.94 (1H, s), 12.06 (1H, brs).

Example 248(4S)-5-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxy-5-oxopentanoicacid (Step 1)

A solution of potassium (S)-5-(tert-butoxy)-4-hydroxy-5-oxopentanoate(390 mg, 1.61 mmol) and benzyl bromide (0.249 mL, 2.09 mmol) in DMF (8mL) was stirred at room temperature for 4 hr. To the reaction mixturewas added water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 3→45% ethyl acetate/hexane) to give 1-tert-butyl (S)-5-benzyl2-hydroxypentanedioate (347 mg, 1.179 mmol, 73.2%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.48 (9H, s), 1.81-1.99 (1H, m), 2.16 (1H,dddd, J=14.0, 8.9, 7.0, 4.2 Hz), 2.37-2.63 (2H, m), 2.86 (1H, d, J=5.3Hz), 4.00-4.14 (1H, m), 5.13 (2H, s), 7.28-7.42 (5H, m).

(Step 2)

Cooled TFA (5 mL) was added to 1-tert-butyl (S)-5-benzyl2-hydroxypentanedioate (347 mg, 1.18 mmol), and the mixture was stirredat 0° C. for 2 hr. The reaction mixture was concentrated under reducedpressure, and the obtained residue was subjected twice to azeotropy withtoluene to give crude (S)-5-(benzyloxy)-2-hydroxy-5-oxopentanoic acid asa colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.90-2.15 (1H, m), 2.34-2.46 (1H, m),2.55-2.67 (2H, m), 4.33 (1H, dd, J=7.7, 4.0 Hz), 5.15 (2H, s), 7.34-7.38(5H, m).

(Step 3)

HATU (86 mg, 0.23 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(80 mg, 0.20 mmol), DIEA (0.039 mL, 0.23 mmol) and(S)-5-(benzyloxy)-2-hydroxy-5-oxopentanoic acid (53.7 mg, 0.23 mmol) inDMF (2 mL) at room temperature, and the mixture was stirred at roomtemperature for 2 hr. To the reaction mixture was added water, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 5→80% ethylacetate/hexane) to give benzyl(S)-5-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxy-5-oxopentanoate(40.0 mg, 0.065 mmol, 32.0%) as a colorless oil.

MS(API): Calculated 610.7. Found 611.4 (M+H).

(Step 4)

A solution of benzyl(S)-5-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxy-5-oxopentanoate(40 mg, 0.07 mmol) and 10% palladium-carbon (6.97 mg, 0.07 mmol, 50%wet) in MeOH (2 mL) was stirred under hydrogen atmosphere (1 atm) atroom temperature for 3 hr. The catalyst was removed by filtration, andthe filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 10→30% MeOH/ethyl acetate) to give the title compound (14.00mg, 0.027 mmol, 41.1%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 0.30 (9H, s), 1.25-1.33 (1H, m), 1.61-1.75(1H, m), 1.79-1.93 (1H, m), 2.21-2.35 (2H, m), 2.76-2.90 (1H, m),3.03-3.17 (1H, m), 3.57-3.70 (1H, m), 3.73 (3H, s), 4.09-4.23 (1H, m),4.46 (1H, dd, J=8.3, 4.2 Hz), 5.57 (1H, s), 6.70-6.95 (2H, m), 7.21 (2H,d, J=9.8 Hz), 7.44 (1H, d, J=9.1 Hz), 10.86 (1H, s), 12.06 (1H, s).

Example 249N-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)-L-alanine

The title compound was synthesized using(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamideand benzyl (S)-2-aminopropanoate, by the reaction and purification inthe same manner as in Step 1 of Example 225 and Step 3 of Example 227.

Example 2505-((5R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-isopropyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-oxopentanoicacid

The title compound was synthesized using(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-isopropyl-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide,by the reaction and purification in the same manner as in Example 82.

¹H NMR (300 MHz, DMSO-d): δ 0.30 (9H, s), 1.20 (6H, d, J=6.8 Hz), 1.73(2H, dq, J=15.3, 7.5 Hz), 2.15-2.32 (2H, m), 2.37-2.66 (2H, m),2.85-3.03 (2H, m), 3.04-3.22 (1H, m), 3.71-3.87 (1H, m), 4.06 (1H, ddd,J=12.6, 7.5, 4.5 Hz), 5.74 (1H, s), 7.13-7.29 (3H, m), 7.80 (1H, d,J=8.3 Hz), 10.87 (1H, s), 12.08 (1H, brs).

Example 2515-((5R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-propyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-oxopentanoicacid

The title compound was synthesized using(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide,by the reaction and purification in the same manner as in Example 82.

¹H NMR (300 MHz, DMSO-d): δ 0.30 (9H, s), 0.86-0.96 (3H, m), 1.52-1.86(4H, m), 2.15-2.33 (3H, m), 2.39-2.58 (1H, m), 2.65 (2H, t, J=7.7 Hz),2.83-3.01 (1H, m), 3.03-3.22 (1H, m), 3.69-3.89 (1H, m), 4.05 (1H, ddd,J=12.7, 7.6, 4.7 Hz), 5.74 (1H, s), 7.05-7.28 (3H, m), 7.78 (1H, d,J=8.3 Hz), 10.87 (1H, s), 12.12 (1H, brs).

Example 2525-((5R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2,3,7,8-tetrahydrofuro[2,3-g]isoquinolin-6(5H)-yl)-5-oxopentanoicacid (Step 1)

Potassium tert-butoxide (22.85 g, 203.61 mmol) was added to a mixture of1,4-dibromo-2-fluorobenzene (14.77 g, 58.17 mmol) in a mixed solvent ofethylene glycol (75 mL, 0.00 mmol) and NMP (7.5 mL) with cooling at roomtemperature, and the mixture was stirred at 100° C. for 15 hr. Thereaction mixture was poured into ice water (600 mL), ethyl acetate(about 200 mL) was added thereto, and the insoluble substance wasremoved by filtration. The organic layer of the filtrate was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The precipitate was washed with hexane to give2-(2,5-dibromophenoxy)ethanol (13.22 g, 44.7 mmol, 77%) as a grayishwhite solid.

¹H NMR (300 MHz, CDCl₃): δ 2.15 (1H, t, J=6.6 Hz), 3.97-4.04 (2H, m),4.13 (2H, t), 7.01 (1H, dd), 7.05 (1H, d, J=1.9 Hz), 7.40 (1H, d, J=8.3Hz).

(Step 2)

Phosphorus tribromide (2.81 mL, 29.91 mmol) was added to a solution of2-(2,5-dibromophenoxy)ethanol (13.21 g, 44.64 mmol) in toluene (100 mL)at room temperature, and the mixture was stirred at 90° C. for 2.5 hr.The reaction mixture was poured into ice water (350 mL), and the mixturewas extracted three times with a mixed solvent of ethyl acetate/hexane(3:1). The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theinsoluble substance was removed by filtration, and washed with a mixedsolvent of ethyl acetate/hexane (1:2), and the filtrate was concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 2→8 ethyl acetate/hexane) togive 1,4-dibromo-2-(2-bromoethoxy)benzene (10.45 g, 29.1 mmol, 65.2%) asa white solid.

¹H NMR (300 MHz, CDCl₃): δ 3.68 (2H, t, J=6.4 Hz), 4.33 (2H, t, J=6.4Hz), 6.99-7.04 (2H, m), 7.38-7.43 (1H, m).

(Step 3)

1.6 M n-Butyllithium/hexane solution (21.84 mL, 34.94 mmol) was slowlyadded to a solution of 1,4-dibromo-2-(2-bromoethoxy)benzene (10.45 g,29.12 mmol) in THF (200 mL) at −78° C. under argon gas atmosphere. Thereaction mixture was stirred at −78° C. for 30 min, and then at 0° C.for 2 hr. The reaction mixture was added to ice water, and 2Nhydrochloric acid was added thereto until the pH of the mixture became3. Then, the mixture was extracted three times with a mixed solvent ofethyl acetate/hexane (3:1). The organic layer was washed with brine, anddried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 2→8% ethyl acetate/hexane) to give6-bromo-2,3-dihydrobenzofuran (4.57 g, 22.96 mmol, 79%) as a whitesolid.

¹H NMR (300 MHz, CDCl₃): δ 3.15 (2H, t, J=8.9 Hz), 4.58 (2H, t, J=8.9Hz), 6.92-6.98 (2H, m), 7.04 (1H, d).

(Step 4)

Magnesium powder (0.668 g, 27.49 mmol) and iodine (7 mg, 0.03 mmol) wereadded to a solution of 6-bromo-2,3-dihydrobenzofuran (4.56 g, 22.91mmol) in THF (40 mL) under argon gas atmosphere at room temperature. Themixture was stirred at 70° C. for 1 hr, 1.2M ethylene oxide/THF solution(25.0 mL, 30.00 mmol) was slowly added thereto at room temperature, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was poured into 1N hydrochloric acid (200 mL) and ice, and themixture was extracted three times with ethyl acetate. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 2→930% ethylacetate/hexane) to give 2-(2,3-dihydrobenzofuran-6-yl)ethanol (2.42 g,14.74 mmol, 64.3%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.41 (1H, t, J=5.1 Hz), 2.82 (2H, t, J=6.4Hz), 3.18 (2H, t, J=8.5 Hz), 3.83 (2H, q, J=6.0 Hz), 4.56 (2H, t, J=8.7Hz), 6.67 (1H, s), 6.71 (1H, d, J=7.6 Hz), 7.13 (1H, d, J=7.6 Hz).

(Step 5)

2.2M DEAD/toluene solution (8.67 mL, 19.08 mmol) was added to a solutionof 2-(2,3-dihydrobenzofuran-6-yl)ethanol (2.41 g, 14.68 mmol) andphthalimide (2.375 g, 16.14 mmol) in THF (32 mL) under argon gasatmosphere at 0° C., and the mixture was stirred at room temperature for15 hr. The reaction mixture was poured into water (120 mL), and themixture was extracted three times with ethyl acetate. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The precipitate was collected byfiltration with diethyl ether to give2-(2-(2,3-dihydrobenzofuran-6-yl)ethyl)isoindoline-1,3-dione (3.04 g,10.36 mmol, 70.6%) as a pale yellow solid.

¹H NMR (300 MHz, CDCl₃): δ 2.93 (2H, t), 3.16 (2H, t, J=8.7 Hz),3.85-3.93 (2H, m), 4.54 (2H, t, J=8.7 Hz), 6.69 (1H, s), 6.74 (1H, dd,J=7.6, 1.5 Hz), 7.09 (1H, d, J=7.6 Hz), 7.67-7.74 (2H, m), 7.80-7.87(2H, m).

(Step 6)

Hydrazine monohydrate (2.505 mL, 51.65 mmol) was added to a solution of2-(2-(2,3-dihydrobenzofuran-6-yl)ethyl)isoindoline-1,3-dione (3.03 g,10.33 mmol) in EtOH (30 mL) at room temperature, and the mixture washeated under reflux for 1 hr. The reaction mixture was cooled, and theinsoluble substance was removed by filtration with diethyl ether. Thefiltrate was concentrated under reduced pressure, and the obtainedresidue was subjected to azeotropy with toluene (about 80 mL). Theobtained residue was purified by silica gel column chromatography(solvent gradient; 10→100% ethyl acetate/hexane) to give2-(2,3-dihydrobenzofuran-6-yl)ethanamine (1.66 g, 10.17 mmol, 98%) as apale yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 1.17 (2H, brs), 2.69 (2H, t), 2.94 (2H, t),3.17 (2H, t, J=8.7 Hz), 4.56 (2H, t, J=8.7 Hz), 6.65 (1H, s), 6.68 (1H,dd), 7.11 (1H, d, J=7.6 Hz).

(Step 7)

6-(tert-Butoxycarbonyl)-2,3,5,6,7,8-hexahydrofuro[2,3-g]isoquinoline-5-carboxylicacid was synthesized using 2-(2,3-dihydrobenzofuran-6-yl)ethanamine, bythe reaction and purification in the same manner as in Steps 3 to 7 ofExample 254 to give.

¹H NMR (300 MHz, CDCl₃): δ 1.41-1.52 (9H, m), 2.68-2.80 (1H, m),2.84-2.97 (1H, m), 3.17 (2H, t, J=8.7 Hz), 3.54 (1H, ddd, J=12.5, 8.1,4.7 Hz), 3.72-3.89 (1H, m), 4.55 (2H, t, J=9.1 Hz), 5.30-5.50 (1H, m),6.57 (1H, s), 7.26 (1H, s)

(Step 8)

(R)—N-(3,5-Difluoro-4-(trimethylsilyl)phenyl)-2,3,5,6,7,8-hexahydrofuro[2,3-g]isoquinoline-5-carboxamidewas synthesized using6-(tert-butoxycarbonyl)-2,3,5,6,7,8-hexahydrofuro[2,3-g]isoquinoline-5-carboxylicacid, by the reaction and purification in the same manner as in Steps 8to 10 of Example 254.

¹H NMR (300 MHz, CDCl₃): δ 0.32 (9H, t, J=1.3 Hz), 2.26 (1H, brs),2.67-2.78 (1H, m), 2.80-2.91 (1H, m), 3.07-3.23 (4H, m), 4.49-4.57 (2H,m), 4.68 (1H, s), 6.52 (1H, s), 7.06-7.14 (2H, m), 7.40 (1H, s), 9.68(1H, s).

(Step 9)

The title compound was synthesized using(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2,3,5,6,7,8-hexahydrofuro[2,3-g]isoquinoline-5-carboxamide,by the reaction and purification in the same manner as in Example 82.

¹H NMR (300 MHz, CDCl₃): δ 0.27 (9H, s), 2.10-2.20 (2H, m), 2.44-2.51(2H, m), 2.53-2.64 (1H, m), 2.78-2.90 (2H, m), 3.08-3.36 (3H, m),3.60-3.70 (1H, m), 3.98-4.08 (1H, m), 4.48-4.62 (2H, m), 5.83 (1H, s),6.61 (1H, s), 6.77-6.86 (2H, m), 7.37 (1H, s), 9.82 (1H, s), 11.23 (1H,brs).

Example 2535-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-5-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

The title compound was synthesized using(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-5-methyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamide,by the reaction and purification in the same manner as in Example 82.

¹H NMR (300 MHz, CDCl₃): δ 0.27 (9H, s), 2.10-2.18 (5H, m), 2.46-2.65(3H, m), 2.84 (1H, dt, J=15.1, 6.2 Hz), 2.96 (1H, dt, J=15.7, 5.0 Hz),3.10-3.21 (1H, m), 3.62-3.74 (1H, m), 3.81 (3H, s), 3.98-4.07 (1H, m),5.86 (1H, s), 6.76 (1H, d, J=8.7 Hz), 6.79-6.86 (2H, m), 7.34 (1H, d,J=8.7 Hz), 9.73 (1H, s), 11.06 (1H, brs).

Example 2545-((6R)-6-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-8,9-dihydro[1,3]dioxolo[4,5-f]isoquinolin-7(6H)-yl)-5-oxopentanoicacid (Step 1)

Benzo[d][1,3]dioxole-4-carbaldehyde (6.13 g, 40.83 mmol), nitromethane(85 mL, 1569.38 mmol) and ammonium acetate (4.72 g, 61.25 mmol) wereheated under reflux for 1 hr. The reaction mixture was cooled, water wasadded thereto, and the mixture was extracted three times with ethylacetate. The organic layer was washed with water and brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The precipitate was washed with ethyl acetate/IPE to give(E)-4-(2-nitrovinyl)benzo[d][1,3]dioxole (6.26 g, 32.4 mmol, 79%) asyellow crystals.

¹H NMR (300 MHz, CDCl₃): δ 6.13 (2H, s), 6.86-6.98 (3H, m), 7.83 (1H,d), 7.92 (1H, d).

(Step 2)

Lithium aluminium hydride (4.91 g, 129.43 mmol) was slowly added to asolution of (E)-4-(2-nitrovinyl)benzo[d][1,3]dioxole (6.25 g, 32.36mmol) in THF (250 mL) at 0° C., and the mixture was stirred at 0° C. 5min, and then at 70° C. for 4 hr. The reaction mixture was cooled to−78° C., 8N aqueous sodium hydroxide solution (130 mL) was slowly addedthereto, and the mixture was stirred at room temperature for 30 min. Theinsoluble substance was removed by filtration, and washed with a mixedsolvent of Et₂O/THF (1:1). The filtrate and washing were combined, andthe aqueous layer was extracted twice with a mixed solvent of Et₂O/THF(1:1). The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography (NH,solvent gradient; 10→100% ethyl acetate/hexane) to give2-(benzo[d][1,3]dioxol-4-yl)ethanamine (1.96 g, 11.87 mmol, 36.7%) as apale yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 1.26 (2H, brs), 2.73 (2H, t), 2.97 (2H, t),5.93 (2H, s), 6.65-6.81 (3H, m).

(Step 3)

Ethyl 2-chloro-2-oxoacetate (1.458 mL, 13.05 mmol) was added to asolution of 2-(benzo[d][1,3]dioxol-4-yl)ethanamine (1.96 g, 11.87 mmol)and TEA (1.819 mL, 13.05 mmol) in THF (30 mL) at 0° C., and the mixturewas stirred at room temperature for 1 hr. To the reaction mixture wasadded aqueous sodium hydrogen carbonate solution, and the mixture wasextracted three times with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 33→55% ethylacetate/hexane) to give ethyl2-((2-(benzo[d][1,3]dioxol-4-yl)ethyl)amino)-2-oxoacetate (2.37 g, 8.93mmol, 75%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 1.37 (3H, t, J=7.2 Hz), 2.87 (2H, t, J=6.8Hz), 3.61 (2H, q, J=6.8 Hz), 4.33 (2H, q, J=7.1 Hz), 5.95 (2H, s), 6.66(1H, dd), 6.74 (1H, dd), 6.79 (1H, t), 7.32 (1H, brs).

(Step 4)

Zinc(II) chloride (0.606 g, 4.45 mmol) was added to a solution of ethyl2-((2-(benzo[d][1,3]dioxol-4-yl)ethyl)amino)-2-oxoacetate (2.36 g, 8.90mmol) and phosphoryl chloride (4.15 mL, 44.48 mmol) in acetonitrile (12mL) at room temperature, and the mixture was heated under reflux for 2hr. To the reaction mixture were added ice and aqueous sodium hydrogencarbonate solution. 8N Aqueous sodium hydroxide solution and potassiumcarbonate were added thereto until the mixture became neutral. Then, themixture was extracted three times with ethyl acetate. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 8→50% ethylacetate/hexane) to give ethyl8,9-dihydro-[1,3]dioxolo[4,5-f]isoquinoline-6-carboxylate (1.99 g, 8.05mmol, 90%) as a yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 1.41 (3H, t, J=7.0 Hz), 2.72 (2H, dd, J=8.3,6.8 Hz), 3.83-3.89 (2H, m), 4.41 (2H, q, J=7.2 Hz), 6.03 (2H, s), 6.74(1H, d, J=8.3 Hz), 7.29 (1H, d, J=8.0 Hz).

(Step 5)

A solution of ethyl8,9-dihydro-[1,3]dioxolo[4,5-f]isoquinoline-6-carboxylate (1.98 g, 8.01mmol) and 20% palladium hydroxide-carbon (0.67 g, 2.20 mmol, 50% wet) inEtOH (40 mL) was stirred under hydrogen atmosphere (1 atm) at roomtemperature for 4 hr. The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (solvent gradient;10→100% ethyl acetate/hexane) to give ethyl6,7,8,9-tetrahydro-[1,3]dioxolo[4,5-f]isoquinoline-6-carboxylate (1.82g, 7.30 mmol, 91%) as a yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 1.30 (3H, t, J=7.2 Hz), 1.97 (1H, brs),2.66-2.73 (2H, m), 3.06 (1H, dt, J=12.8, 5.7 Hz), 3.23-3.33 (1H, m),4.22 (2H, qd, J=7.2, 1.9 Hz), 4.66 (1H, s), 5.95 (2H, dd, J=7.6, 1.5Hz), 6.68 (1H, d, J=7.9 Hz), 6.84 (1H, d, J=7.9 Hz).

(Step 6)

Boc₂O (1.664 g, 7.62 mmol) was added to a solution of ethyl6,7,8,9-tetrahydro-[1,3]dioxolo[4,5-f]isoquinoline-6-carboxylate (1.81g, 7.26 mmol) in THF (25 mL) at room temperature, and the mixture wasstirred at room temperature for 4 hr. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (solvent gradient; 2→20%ethyl acetate/hexane) to give 6-ethyl 7-tert-butyl8,9-dihydro-[1,3]dioxolo[4,5-f]isoquinoline-6,7(6H)-dicarboxylate (2.45g, 7.01 mmol, 97%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.23-1.29 (3H, m), 1.45-1.51 (9H, m),2.76-2.87 (2H, m), 3.67-3.88 (2H, m), 4.11-4.20 (2H, m), 5.35-5.56 (1H,m), 5.96 (2H, d, J=6.8 Hz), 6.71 (1H, d, J=7.9 Hz), 6.95-7.03 (1H, m).

(Step 7)

2N aqueous lithium hydroxide solution (22.41 mL, 44.82 mmol) was addedto a solution of 6-ethyl 7-tert-butyl8,9-dihydro-[1,3]dioxolo[4,5-f]isoquinoline-6,7(6H)-dicarboxylate (2.61g, 7.47 mmol) in a mixed solvent of EtOH (11 mL) and THF (11 mL) at roomtemperature, and the mixture was stirred at room temperature for 2 hr.To the reaction mixture was added water, and 2N hydrochloric acid wasadded thereto until the pH of the mixture became 3. Then, the mixturewas extracted three times with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure to give7-(tert-butoxycarbonyl)-6,7,8,9-tetrahydro-[1,3]dioxolo[4,5-f]isoquinoline-6-carboxylicacid (2.14 g, 6.66 mmol, 89%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.42-1.52 (9H, m), 2.81 (2H, brs), 3.65-3.81(2H, m), 5.35-5.58 (1H, m), 5.96 (2H, dd, J=9.1, 1.5 Hz), 6.71 (1H, d,J=7.9 Hz), 6.97 (1H, d, J=7.9 Hz).

(Step 8)

T3P (2.97 mL, 4.99 mmol) was added to a solution of7-(tert-butoxycarbonyl)-6,7,8,9-tetrahydro-[1,3]dioxolo[4,5-f]isoquinoline-6-carboxylicacid (1.07 g, 3.33 mmol), 3,5-difluoro-4-(trimethylsilyl)aniline (0.704g, 3.50 mmol), DIEA (2.90 mL, 16.65 mmol) and DMAP (0.447 g, 3.66 mmol)in ethyl acetate (24 mL), and the mixture was stirred at 65° C. for 15hr. To the reaction mixture was added water, and the mixture wasextracted three times with ethyl acetate. The organic layer was washedwith 10% aqueous citric acid solution, aqueous sodium hydrogen carbonatesolution and brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The precipitate was washed withIPE/hexane to give tert-butyl6-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-8,9-dihydro-[1,3]dioxolo[4,5-f]isoquinoline-7(6H)-carboxylate(1.16 g, 2.299 mmol, 69.0%) as grayish white crystals.

¹H NMR (300 MHz, CDCl₃): δ 0.32 (9H, t, J=1.3 Hz), 1.53 (9H, s), 2.83(2H, t, J=5.9 Hz), 3.58 (1H, brs), 3.71-3.81 (1H, m), 5.63 (1H, brs),5.98 (2H, dd, J=11.3, 1.5 Hz), 6.71-6.81 (2H, m), 6.96-7.05 (2H, m),9.06 (1H, brs).

(Step 9)

tert-Butyl6-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-8,9-dihydro-[1,3]dioxolo[4,5-f]isoquinoline-7(6H)-carboxylate(1.16 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-6-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-8,9-dihydro-[1,3]dioxolo[4,5-f]isoquinoline-7(6H)-carboxylate(0.58 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-6-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-8,9-dihydro-[1,3]dioxolo[4,5-f]isoquinoline-7(6H)-carboxylate(0.56 g, >99% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALPAK AD (NF001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 10)

Cooled TFA (7.5 mL) was added to tert-butyl(R)-6-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-8,9-dihydro-[1,3]dioxolo[4,5-f]isoquinoline-7(6H)-carboxylate(568 mg, 1.13 mmol), and the mixture was stirred at room temperature for3 min. The reaction mixture was added to ice and aqueous sodium hydrogencarbonate solution, and potassium carbonate was added thereto until thepH of the mixture became 8. Then, the mixture was extracted three timeswith ethyl acetate. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure to give(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6,7,8,9-tetrahydro-[1,3]dioxolo[4,5-f]isoquinoline-6-carboxamide(400 mg, 0.989 mmol, 88%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.32 (9H, t, J=1.3 Hz), 2.09 (1H, brs),2.65-2.83 (2H, m), 3.05-3.20 (2H, m), 4.62 (1H, s), 5.95 (2H, dd, J=9.1,1.5 Hz), 6.72 (1H, d, J=8.3 Hz), 7.03-7.13 (3H, m), 9.42 (1H, s).

(Step 11)

Dihydro-2H-pyran-2,6(3H)-dione (48.9 mg, 0.43 mmol) was added to asolution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6,7,8,9-tetrahydro-[1,3]dioxolo[4,5-f]isoquinoline-6-carboxamide(133 mg, 0.33 mmol) and TEA (69 μL, 0.50 mmol) in THF (3.2 mL) at roomtemperature, and the mixture was stirred at room temperature for 4 hr.To the reaction mixture was added water, and 2N hydrochloric acid wasadded thereto until the pH of the mixture became 4. Then, the mixturewas extracted three times with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (Diol, solvent gradient; 30→100% ethylacetate/hexane) to give the title compound (141.6 mg, 0.273 mmol, 83%)as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.27 (9H, s), 2.08-2.19 (2H, m), 2.38-2.63(3H, m), 2.85-3.01 (2H, m), 3.13-3.24 (1H, m), 3.72 (1H, ddd, J=12.3,8.5, 4.2 Hz), 4.03-4.11 (1H, m), 5.85 (1H, s), 5.97 (2H, dd, J=12.7, 1.3Hz), 6.71 (1H, d, J=7.9 Hz), 6.74-6.82 (2H, m), 7.07 (1H, d, J=8.3 Hz),9.83 (1H, s), 11.30 (1H, brs).

Example 2555-((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2,3,7,8-tetrahydrofuro[2,3-g]isoquinolin-6(5H)-yl)-5-oxopentanoicacid (Step 1)

(R)—N-(7-Fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2,3,5,6,7,8-hexahydrofuro[2,3-g]isoquinoline-5-carboxamidewas synthesized using6-(tert-butoxycarbonyl)-2,3,5,6,7,8-hexahydrofuro[2,3-g]isoquinoline-5-carboxylicacid and 7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-aminehydrochloride, by the reaction and purification in the same manner as inStep 8 of Example 252.

¹H NMR (300 MHz, CDCl₃): δ 1.33 (6H, s), 1.90 (2H, t, J=7.4 Hz),2.65-2.92 (5H, m), 3.04-3.20 (4H, m), 4.53 (2H, t, J=9.1 Hz), 4.66 (1H,s), 6.52 (1H, s), 7.12-7.20 (2H, m), 7.43 (1H, s), 9.46 (1H, s).

(Step 2)

The title compound was synthesized using(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2,3,5,6,7,8-hexahydrofuro[2,3-g]isoquinoline-5-carboxamide,by the reaction and purification in the same manner as in Step 9 ofExample 252.

¹H NMR (300 MHz, CDCl₃): δ 1.29 (6H, s), 1.85 (2H, t, J=7.4 Hz),2.05-2.14 (2H, m), 2.48 (2H, t, J=6.8 Hz), 2.61 (2H, td, J=7.0, 3.0 Hz),2.76-2.89 (3H, m), 3.08-3.21 (3H, m), 3.65 (1H, ddd, J=12.2, 7.8, 4.5Hz), 3.89 (1H, ddd, J=11.9, 6.8, 4.7 Hz), 4.49-4.59 (2H, m), 5.93 (1H,s), 6.61 (1H, s), 6.96 (1H, s), 7.07 (1H, dd, J=11.7, 1.5 Hz), 7.19 (1H,s), 9.26 (1H, s), 10.86 (1H, brs).

Example 2565-((6R)-6-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-8,9-dihydro[1,3]dioxolo[4,5-f]isoquinolin-7(6H)-yl)-5-oxopentanoicacid (Step 1)

T3P (2.94 mL, 4.95 mmol) was added to a solution of7-(tert-butoxycarbonyl)-6,7,8,9-tetrahydro-[1,3]dioxolo[4,5-f]isoquinoline-6-carboxylicacid (1.06 g, 3.30 mmol),7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine hydrochloride (0.747g, 3.46 mmol), DIEA (2.87 mL, 16.49 mmol) and DMAP (0.443 g, 3.63 mmol)in ethyl acetate (24 mL), and the mixture was stirred at 65° C. for 15hr. To the reaction mixture was added water, and the mixture wasextracted three times with ethyl acetate. The organic layer was washedwith 10% aqueous citric acid solution, aqueous sodium hydrogen carbonatesolution and brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The precipitate was washed withIPE/hexane to give tert-butyl6-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-8,9-dihydro-[1,3]dioxolo[4,5-f]isoquinoline-7(6H)-carboxylate(1.44 g, 2.98 mmol, 90%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.33 (6H, s), 1.52 (9H, s), 1.90 (2H, t,J=7.4 Hz), 2.78-2.89 (4H, m), 3.55 (1H, brs), 3.79 (1H, dt, J=12.4, 6.1Hz), 5.63 (1H, brs), 5.97 (2H, dd, J=11.0, 1.5 Hz), 6.71-6.80 (2H, m),7.04-7.11 (2H, m), 8.71 (1H, brs).

(Step 2)

tert-Butyl6-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-8,9-dihydro-[1,3]dioxolo[4,5-f]isoquinoline-7(6H)-carboxylate(1.43 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-6-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-8,9-dihydro-[1,3]dioxolo[4,5-f]isoquinoline-7(6H)-carboxylate(0.70 g, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-6-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-8,9-dihydro-[1,3]dioxolo[4,5-f]isoquinoline-7(6H)-carboxylate(0.68 g, >99% ee), each as a white solid.

purification condition by chiral column chromatography

column: CHIRALPAK AD (NF001) 50 mmID×500 mmL

solvent: hexane/EtOH=800/200

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

Cooled TFA (9 mL) was added to tert-butyl(R)-6-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-8,9-dihydro-[1,3]dioxolo[4,5-f]isoquinoline-7(6H)-carboxylate(692 mg, 1.43 mmol), and the mixture was stirred at room temperature for15 min. The reaction mixture was added to ice and aqueous sodiumhydrogen carbonate solution, and potassium carbonate was added theretountil the pH of the mixture became 8. Then, the mixture was extractedthree times with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure to give(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6,7,8,9-tetrahydro-[1,3]dioxolo[4,5-f]isoquinoline-6-carboxamide(541 mg, 1.415 mmol, 99%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.33 (6H, s), 1.90 (2H, t, J=7.4 Hz), 2.12(1H, brs), 2.64-2.82 (2H, m), 2.87 (2H, t, J=7.4 Hz), 3.12 (2H, t, J=5.9Hz), 4.61 (1H, s), 5.95 (2H, dd, J=7.9, 1.5 Hz), 6.71 (1H, d, J=8.3 Hz),7.07 (1H, d, J=8.3 Hz), 7.11-7.17 (2H, m), 9.19 (1H, s).

(Step 4)

Dihydro-2H-pyran-2,6(3H)-dione (48.9 mg, 0.43 mmol) was added to asolution of(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6,7,8,9-tetrahydro-[1,3]dioxolo[4,5-f]isoquinoline-6-carboxamide(126 mg, 0.33 mmol) and TEA (69 μL, 0.50 mmol) in THF (3.2 mL) at roomtemperature, and the mixture was stirred at room temperature for 4 hr.To the reaction mixture was added water, and 2N hydrochloric acid wasadded thereto until the pH of the mixture became 4. Then, the mixturewas extracted three times with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (Diol, solvent gradient; 30→100% ethylacetate/hexane) to give the title compound (132.5 mg, 0.267 mmol, 81.)as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.28 (6H, s), 1.85 (2H, t, J=7.4 Hz),2.06-2.14 (2H, m), 2.48 (2H, t), 2.52-2.75 (2H, m), 2.80 (2H, t, J=7.4Hz), 2.84-2.95 (1H, m), 3.01-3.12 (1H, m), 3.74 (1H, ddd, J=12.3, 7.2,5.1 Hz), 3.86-3.97 (1H, m), 5.94-6.00 (3H, m), 6.72 (1H, d, J=7.9 Hz),6.90 (1H, d, J=8.3 Hz), 6.92 (1H, d, J=0.8 Hz), 7.05 (1H, dd, J=11.7,1.5 Hz), 9.21 (1H, s), 10.69 (1H, brs).

Example 257N-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)-N-methyl-beta-alanine

The title compound was synthesized using benzyl3-(methylamino)propanoate hydrochloride and(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide,by the reaction and purification in the same manner as in Step 1 ofExample 225 and Step 3 of Example 227.

¹H NMR (300 MHz, DMSO-d): δ 0.30 (9H, s), 2.43-2.54 (2H, m), 2.80 (3H,s), 2.83-3.04 (2H, m), 3.26-3.40 (2H, m), 3.42-3.54 (1H, m), 3.72 (3H,s), 3.82-3.97 (1H, m), 5.13 (1H, s), 6.74-6.84 (2H, m), 7.23 (2H, d,J=9.8 Hz), 7.30-7.37 (1H, m), 10.70 (1H, s), 12.25 (1H, brs).

[α]_(D) ²⁵ +65.9 (C 0.2500, MeOH)

Example 2581-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)azetidine-3-carboxylicacid

The title compound was synthesized using benzyl azetidine-3-carboxylateand(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide,by the reaction and purification in the same manner as in Step 1 ofExample 225 and Step 3 of Example 227.

¹H NMR (300 MHz, DMSO-d₆): δ 0.29 (9H, s), 2.69-2.84 (1H, m), 2.99-3.16(1H, m), 3.29-3.45 (2H, m), 3.72 (3H, s), 3.75-3.85 (1H, m), 3.90 (1H,dd, J=8.1, 6.2 Hz), 3.95-4.14 (2H, m), 4.22 (1H, t, J=8.7 Hz), 5.31 (1H,s), 6.76-6.85 (2H, m), 7.15-7.25 (2H, m), 7.39-7.50 (1H, m), 10.67 (1H,s), 12.61 (1H, brs).

Example 2591-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)azetidine-3-carboxylicacid

The title compound was synthesized using benzyl azetidine-3-carboxylateand(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide,by the reaction and purification in the same manner as in Step 1 ofExample 225 and Step 3 of Example 227.

¹H NMR (300 MHz, DMSO-d): δ 0.29 (9H, s), 1.29 (3H, t, J=6.8 Hz),2.68-2.83 (1H, m), 2.99-3.13 (1H, m), 3.35-3.44 (2H, m), 3.73-3.85 (1H,m), 3.90 (1H, dd, J=7.9, 6.0 Hz), 3.95-4.05 (3H, m), 4.06-4.14 (1H, m),4.21 (1H, t, J=8.7 Hz), 5.31 (1H, s), 6.75-6.83 (2H, m), 7.15-7.24 (2H,m), 7.39-7.46 (1H, m), 10.67 (1H, s), 12.59 (1H, brs).

Example 260(1-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)azetidin-3-yl)aceticacid (Step 1)

A solution of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid (10.13g, 47.06 mmol), benzyl bromide (6.72 mL, 56.47 mmol) and cesiumcarbonate (18.40 g, 56.47 mmol) in DMF (30 mL) was stirred at roomtemperature for 14 hr. To the reaction mixture was added water, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 5→30% ethylacetate/hexane) to give a colorless oil (14.86 g). Cooled TFA (50 mL)was added to a mixture of the colorless oil (14.86 g) intrifluoromethylbenzene (3.75 mL) at 5° C., and the mixture was stirredat room temperature for 10 min. The reaction mixture was added to acooled mixture of potassium carbonate (90 g), water (500 mL) and ethylacetate (100 mL). Saturated brine (50 mL) was added thereto, and themixture was extracted three times with a mixed solvent of ethylacetate/THF (3:1). The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure to give a colorless oil (3.34 g). To the aqueous layer wasadded potassium carbonate (110 g), and the mixture was extracted twicewith a mixed solvent of ethyl acetate/THF (3:1). The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure to give a colorless oil (4.908 g). Theobtained colorless oil (8.248 g) was dissolved in ethyl acetate, and thesolution was dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure to give benzyl2-(azetidin-3-yl)acetate (6.81 g, 33.2 mmol, 70.5%) as a pale brownsolid.

¹H NMR (300 MHz, CDCl₃): δ 2.75 (s, 2H) 3.14-3.36 (m, 1H) 3.73-3.91 (m,2H) 4.04-4.22 (m, 2H) 5.10 (s, 2H) 7.26-7.45 (m, 5H)

(Step 2)

A solution of bis(trichloromethyl) carbonate (228 mg, 0.77 mmol) in THF(2 mL) was added to a solution of benzyl 2-(azetidin-3-yl)acetate (158mg, 0.77 mmol) and pyridine (0.124 mL, 1.54 mmol) in THF (2 mL) at 5°C., and the mixture was stirred at 5° C. for 30 min. The reactionmixture was concentrated under reduced pressure, the obtained residuewas dissolved in DMF (2 mL), and the solution was cooled to 0° C. Asolution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(200 mg, 0.51 mmol) and DIEA (0.447 mL, 2.56 mmol) in DMF (2 mL) wasadded thereto, and the mixture was stirred at room temperature for 2 hr.To the reaction mixture was added aqueous sodium hydrogen carbonatesolution, and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent; ethylacetate/hexane) to give benzyl(R)-2-(1-(1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)azetidin-3-yl)acetate(47.3 mg, 0.076 mmol, 14.85%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.31 (9H, t, J=1.3 Hz), 2.66-2.77 (2H, m),2.86 (2H, t, J=5.9 Hz), 2.92-3.09 (1H, m), 3.35-3.58 (2H, m), 3.67 (1H,dd, J=8.7, 5.7 Hz), 3.80 (3H, s), 3.91 (1H, dd, J=8.7, 5.7 Hz),4.08-4.17 (1H, m), 4.37 (1H, t, J=8.7 Hz), 5.12 (2H, s), 5.58 (1H, s),6.72 (1H, d, J=2.6 Hz), 6.82 (1H, dd, J=8.3, 2.6 Hz), 7.01-7.11 (3H, m),7.28-7.42 (5H, m), 10.05 (1H, s).

(Step 3)

A solution of benzyl(R)-2-(1-(1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)azetidin-3-yl)acetate(45 mg, 0.07 mmol) and 10% palladium-carbon (10 mg, 0.09 mmol, 50% wet)in MeOH (2 mL) was stirred overnight under hydrogen atmosphere (1 atm)at room temperature. The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (solvent gradient;20→90% ethyl acetate/hexane) to give the title compound (26.6 mg, 0.050mmol, 69.1%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 0.29 (9H, s), 2.57 (2H, d, J=7.6 Hz),2.68-2.85 (2H, m), 2.97-3.13 (1H, m), 3.35-3.42 (1H, m), 3.46-3.58 (1H,m), 3.67-3.86 (5H, m), 3.90-4.02 (1H, m), 4.15 (1H, t, J=8.1 Hz), 5.31(1H, s), 6.76-6.85 (2H, m), 7.15-7.24 (2H, m), 7.38-7.47 (1H, m), 10.65(1H, s), 12.21 (1H, brs).

[α]_(D) ²⁵ −10.5 (c 0.2540, MeOH)

Example 2615-((1R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-methoxy-5-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoicacid

The title compound was synthesized using2-(3-methoxy-2-methylphenyl)ethanamine, by the reaction and purificationin the same manner as in Steps 3 to 11 of Example 254.

¹H NMR (300 MHz, CDCl₃): δ 1.29 (6H, s), 1.85 (2H, t, J=7.4 Hz),2.02-2.11 (2H, m), 2.15 (3H, s), 2.49 (2H, t, J=6.8 Hz), 2.61 (2H, t),2.80 (2H, t, J=7.4 Hz), 2.84-2.95 (1H, m), 2.97-3.08 (1H, m), 3.62-3.77(1H, m), 3.81 (3H, s), 3.82-3.92 (1H, m), 5.97 (1H, s), 6.77 (1H, d,J=8.7 Hz), 6.97 (1H, s), 7.08 (1H, dd, J=11.9, 1.3 Hz), 7.17 (1H, d,J=8.3 Hz), 9.14 (1H, s), 10.82 (1H, brs).

Example 2625-((1R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-propyl-3,4-dihydroisoquinolin-2(H)-yl)-5-oxopentanoicacid

The title compound was synthesized using 2-(3-propylphenyl)ethanamine,by the reaction and purification in the same manner as in Steps 3 to 11of Example 254.

¹H NMR (300 MHz, CDCl₃): δ 0.93 (3H, t, J=7.4 Hz), 1.28 (6H, s), 1.62(2H, sxt, J=7.5 Hz), 1.85 (2H, t, J=7.4 Hz), 2.05-2.14 (2H, m), 2.48(2H, t, J=6.8 Hz), 2.54 (2H, t), 2.62 (2H, td, J=7.0, 3.8 Hz), 2.79 (2H,t, J=7.4 Hz), 2.84-2.93 (1H, m), 3.10-3.21 (1H, m), 3.72 (1H, ddd,J=12.2, 7.5, 4.5 Hz), 3.93 (1H, ddd, J=12.0, 7.3, 4.5 Hz), 5.98 (1H, s),6.96 (1H, s), 7.00 (1H, s), 7.03-7.10 (2H, m), 7.29 (1H, d, J=7.9 Hz),9.29 (1H, s), 10.90 (1H, brs).

Example 263 benzylN-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)glycinate

The title compound was synthesized using(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamideand benzyl 2-(((4-nitrophenoxy)carbonyl)amino)acetate, by the reactionand purification in the same manner as in Step 1 of Example 242.

¹H NMR (300 MHz, CDCl₃): δ 0.30 (t, J=1.32 Hz, 9H), 2.84 (dt, J=15.30,4.44 Hz, 1H), 3.17 (ddd, J=15.20, 10.10, 5.29 Hz, 1H), 3.41 (td,J=10.20, 4.53 Hz, 1H), 3.70-3.82 (m, 4H), 4.14-4.18 (m, 2H), 5.21 (d,J=2.64 Hz, 2H), 5.28-5.38 (m, 1H), 5.74-5.79 (m, 1H), 6.72-6.84 (m, 2H)6.90-7.05 (m, 2H), 7.22 (d, J=8.31 Hz, 1H), 7.30-7.39 (m, 5H), 9.63 (s,1H)

Example 264N-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)glycine

The title compound was synthesized using benzyl(R)-2-(1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxamide)acetate,by the reaction and purification in the same manner as in Step 2 ofExample 242.

¹H NMR (300 MHz, CDCl₃): δ 0.29 (t, J=1.32 Hz, 9H), 2.77-2.93 (m, 1H),3.04-3.24 (m, 1H) 3.34-3.50 (m, 1H), 3.80 (s, 4H), 4.08-4.12 (m, 2H),5.37-5.49 (m, 1H), 5.74 (s, 1H), 6.72-6.86 (m, 2H), 6.94-7.07 (m, 2H),7.21 (d, J=8.31 Hz, 1H), 9.27 (brs, 1H) (The exchangeable 1H was notobserved)

Example 265(4S)-5-((1R)-6-ethoxy-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-methyl-5-oxopentanoicacid Example 266(2S)-5-((1R)-6-ethoxy-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-methyl-5-oxopentanoicacid

The title compound was synthesized using(R)-6-ethoxy-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride and (S)-(+)-2-methylglutaric acid, by the reaction andpurification in the same manner as in Example 240.

The Compound of Example 265

¹H NMR (300 MHz, DMSO-d): δ 1.04 (3H, d, J=6.8 Hz), 1.25-1.34 (9H, m),1.46-1.64 (1H, m), 1.70-1.91 (3H, m), 2.09-2.20 (2H, m), 2.71-2.99 (4H,m), 3.03-3.17 (1H, m), 3.56-3.69 (1H, m), 3.92-4.15 (3H, m), 5.60-5.71(1H, m), 6.74-6.83 (2H, m), 7.13-7.26 (2H, m), 7.41-7.49 (1H, m), 10.44(1H, s), 12.08 (1H, brs).

The Compound of Example 266

¹H NMR (300 MHz, DMSO-d₆): δ 1.09 (3H, d, J=7.2 Hz), 1.24-1.34 (9H, m),1.48-1.66 (1H, m), 1.73-1.91 (3H, m), 2.24-2.48 (3H, m), 2.69-2.90 (3H,m), 3.01-3.19 (1H, m), 3.44-3.59 (1H, m), 3.92-4.08 (3H, m), 5.64 (1H,s), 6.74-6.82 (2H, m), 7.12-7.26 (2H, m), 7.40-7.49 (1H, m), 10.41 (1H,s), 12.14 (1H, brs).

[α]_(D) ²⁵ +10.4 (c 0.2520, MeOH)

Example 267((1-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)azetidin-3-yl)oxy)acetic acid (Step 1)

Sodium hydride (60% oil, 163 mg, 4.06 mmol) was added to a solution oftert-butyl 3-hydroxyazetidine-1-carboxylate (640 mg, 3.69 mmol) andbenzyl 2-bromoacetate (0.644 mL, 4.06 mmol) in DMF (10 mL) at 0° C., andthe mixture was stirred overnight at 0° C. to room temperature. To thereaction mixture were added water and 2N hydrochloric acid, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 3→20% ethylacetate/hexane) to give tert-butyl3-(2-(benzyloxy)-2-oxoethoxy)azetidine-1-carboxylate (1 g, 3.11 mmol,84%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 1.38-1.47 (9H, m), 3.91 (2H, dd, J=10.2, 4.5Hz), 4.01-4.14 (4H, m), 4.27-4.39 (1H, m), 5.19 (2H, s), 7.28-7.45 (5H,m).

(Step 2)

Cooled TFA (5 mL) was added to tert-butyl3-(2-(benzyloxy)-2-oxoethoxy)azetidine-1-carboxylate (1 g, 3.11 mmol) at0° C., and the mixture was stirred at 0° C. for 1 hr. The reactionmixture was added to aqueous sodium hydrogen carbonate solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over sodium sulfate, and the solvent wasevaporated under reduced pressure to give benzyl2-(azetidin-3-yloxy)acetate (0.69 g, 3.12 mmol, 100%) as an orange oil.

MS(API): Calculated 221.3. Found 222.2 (M+H).

(Step 3)

The title compound was synthesized using(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamideand benzyl 2-(azetidin-3-yloxy)acetate, by the reaction and purificationin the same manner as in Example 240.

¹H NMR (300 MHz, DMSO-d): δ 0.29 (9H, s), 2.73-2.85 (1H, m), 2.96-3.16(1H, m), 3.32-3.44 (1H, m), 3.68-3.84 (6H, m), 3.85-4.05 (4H, m),4.11-4.27 (1H, m), 4.28-4.45 (1H, m), 5.32 (1H, s), 6.66-6.86 (2H, m),7.21 (2H, d, J=9.8 Hz), 7.35-7.52 (1H, m), 10.69 (1H, s).

Example 268(4R)-5-((1R)-6-ethoxy-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-methyl-5-oxopentanoicacid Example 269(2R)-5-((1R)-6-ethoxy-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-methyl-5-oxopentanoicacid

The title compound was synthesized using(R)-6-ethoxy-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamidehydrochloride and (R)-(−)-2-methylglutaric acid, by the reaction andpurification in the same manner as in Example 240.

The Compound of Example 268

¹H NMR (300 MHz, CDCl₃): δ 1.21 (3H, d, J=6.4 Hz), 1.29 (6H, s), 1.40(3H, t, J=7.0 Hz), 1.80-1.93 (3H, m), 2.08-2.23 (1H, m), 2.34-2.57 (2H,m), 2.79 (3H, s), 2.99-3.24 (2H, m), 3.64-3.80 (1H, m), 3.94-4.08 (3H,m), 6.01 (1H, s), 6.65-6.84 (2H, m), 6.99 (1H, s), 7.06 (1H, d, J=12.1Hz), 7.33 (1H, d, J=8.7 Hz), 9.35 (1H, s)

The Compound of Example 269

¹H NMR (300 MHz, CDCl₃): δ 1.19 (3H, d, J=6.8 Hz), 1.24-1.31 (6H, m),1.40 (3H, s), 1.84 (2H, s), 1.89-2.02 (1H, m), 2.10-2.28 (1H, m), 2.78(6H, d, J=2.3 Hz), 3.16-3.31 (1H, m), 3.62-3.77 (1H, m), 4.02 (3H, d,J=7.2 Hz), 5.95 (1H, s), 6.68-6.81 (2H, m), 6.88 (1H, s), 6.97-7.06 (1H,m), 7.35 (1H, d, J=8.3 Hz), 9.33 (1H, s)

Example 2705-((5R)-2-(difluoromethoxy)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-oxopentanoicacid (Step 1)

Using a light-resistant reaction container, silver(I) carbonate (12.83g, 46.53 mmol) was added to 5-ethyl 6-tert-butyl2-hydroxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (7.50 g,23.27 mmol) and sodium 2-chloro-2,2-difluoroacetate (21.28 g, 139.60mmol) in a mixed solvent of THF (160 mL) and DMF (160 mL), and themixture was stirred at 90° C. for 15 hr. To the reaction mixture wasadded water, and the mixture was extracted three times with ethylacetate. The insoluble substance was removed by filtration. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 5→30%ethyl acetate/hexane) to give 5-ethyl 6-tert-butyl2-(difluoromethoxy)-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate(1.52 g, 4.08 mmol, 17.54%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 1.22-1.31 (3H, m), 1.45-1.52 (9H, m),2.86-2.98 (2H, m), 3.50-3.67 (1H, m), 4.06-4.24 (3H, m), 5.39-5.62 (1H,m), 6.77 (1H, d, J=8.3 Hz), 7.22-7.74 (1H, m), 7.87 (1H, dd, J=8.5, 5.5Hz).

(Step 2)

6-(tert-Butoxycarbonyl)-2-(difluoromethoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylicacid was synthesized using2-(difluoromethoxy)-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate,by the reaction and purification in the same manner as in Step 7 ofExample 254.

MS(API): Calculated 344.3. Found 345.2 (M+H).

(Step 3)

The title compound was synthesized using6-(tert-butoxycarbonyl)-2-(difluoromethoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylicacid, by the reaction and purification in the same manner as in Steps 8to 11 of Example 254.

¹H NMR (300 MHz, CDCl₃): δ 0.27 (9H, s), 2.06-2.24 (2H, m), 2.34-2.46(2H, m), 2.47-2.61 (1H, m), 3.01-3.15 (2H, m), 3.27-3.39 (1H, m),3.93-4.04 (1H, m), 4.15-4.26 (1H, m), 5.88 (1H, s), 6.66-6.74 (2H, m),6.79 (1H, d, J=8.7 Hz), 7.48 (1H, t), 7.96 (1H, d, J=8.7 Hz), 10.04 (1H,s), 11.54 (1H, brs).

Example 271(1-(((6R)-6-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-8,9-dihydro[1,3]dioxolo[4,5-f]isoquinolin-7(6H)-yl)carbonyl)azetidin-3-yl)aceticacid

The title compound was synthesized using (R)—N-(7-fluoro-1,l-dimethyl-2,3-dihydro-1H-inden-5-yl)-6,7,8,9-tetrahydro-[1,3]dioxolo[4,5-f]isoquinoline-6-carboxamide,by the reaction and purification in the same manner as in Example 230and Example 231.

Example 272(1-(((6R)-6-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-8,9-dihydro[1,3]dioxolo[4,5-f]isoquinolin-7(6H)-yl)carbonyl)azetidin-3-yl)aceticacid (Step 1)

A solution of pyridine (79 mg, 1.00 mmol) in THF (0.5 mL) was added to asolution of benzyl 2-(azetidin-3-yl)acetate (103 mg, 0.50 mmol) andbis(trichloromethyl) carbonate (149 mg, 0.50 mmol) in THF (1 mL) at 0°C., and the mixture was stirred at room temperature for 30 min. Thereaction mixture was concentrated under reduced pressure, the obtainedresidue was dissolved in DMF (2 mL), and the solution was cooled to 0°C. A solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6,7,8,9-tetrahydro-[1,3]dioxolo[4,5-f]isoquinoline-6-carboxamide(202 mg, 0.50 mmol) and DIEA (646 mg, 5.00 mmol) in DMF (1 mL) was addedthereto at 0° C., and the mixture was stirred at 0° C. for 2 hr. Theproduct (obtained in the same manner as above from a solution ofpyridine (79 mg, 1.00 mmol) in THF (0.5 mL) and a solution of2-(azetidin-3-yl)benzyl acetate (103 mg, 0.50 mmol) andbis(trichloromethyl) carbonate (149 mg, 0.50 mmol) in THF (1 mL)) wasdissolved in DMF (2 mL), the solution was added to the reaction mixtureat 0° C., and the mixture was stirred at 0° C. for 2 hr. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 0→100%ethyl acetate/hexane) to give benzyl(R)-2-(1-(6-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6,7,8,9-tetrahydro-[1,3]dioxolo[4,5-f]isoquinoline-7-carbonyl)azetidin-3-yl)acetate(280.0 mg, 88.0%) as a colorless oil.

MS(API): Calculated 635.7. Found 636.4 (M+H).

(Step 2)

A solution of benzyl(R)-2-(1-(6-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6,7,8,9-tetrahydro-[1,3]dioxolo[4,5-f]isoquinoline-7-carbonyl)azetidin-3-yl)acetate(280.0 mg, 0.44 mmol) and 10% palladium-carbon (280.0 mg, 50% wet) inMeOH (2 mL) was stirred under hydrogen atmosphere (1 atm) at roomtemperature for 0.5 hr. The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (solvent gradient;1→100% ethyl acetate/hexane) to give the title compound (180 mg, 0.33mmol, 74.9%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 0.30 (s, 9H), 2.57 (d, J=8.0 Hz, 2H),2.69-2.82 (m, 1H), 2.89-2.94 (m, 1H), 3.37-3.46 (m, 1H), 3.54 (dd,J=6.0, 1.5 Hz, 1H), 3.72 (dd, J=6.0, 1.5 Hz, 1H), 3.76-3.82 (m, 1H),3.96 (t, J=7.5 Hz, 1H), 4.15 (t, J=7.5 Hz, 1H), 5.34 (s, 1H), 6.02 (dd,J=8.3, 0.8 Hz, 2H), 6.82 (d, J=8.3 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H), 7.21(d, J=7.8 Hz, 2H), 10.67 (s, 1H), 12.21 (s, 1H)

[α]_(D) ²⁵ +30.7 (c 0.2515, MeOH)

Example 273(1-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)azetidin-3-yl)aceticacid (Step 1)

Pyridine (194 μL, 2.40 mmol) was added to a solution of2-(azetidin-3-yl)benzyl acetate (246 mg, 1.20 mmol) andbis(trichloromethyl) carbonate (355 mg, 1.20 mmol) in THF (6.5 mL) at 0°C., and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was concentrated under reduced pressure. To theobtained residue was added a solution of(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(177 mg, 0.48 mmol) and DIEA (835 μL, 4.79 mmol) in DMF (6.5 mL) at 0°C., and the mixture was stirred at 0° C. for 2.5 hr. To the reactionmixture was added water, and 2N hydrochloric acid was added theretountil the pH of the mixture became 3. The mixture was extracted withethyl acetate. The organic layer was washed with aqueous sodium hydrogencarbonate solution and brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 37→58%ethyl acetate/hexane) to give benzyl(R)-2-(1-(5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)azetidin-3-yl)acetate(155 mg, 0.258 mmol, 53.9%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.33 (6H, s), 1.90 (2H, t, J=7.4 Hz),2.64-2.79 (2H, m), 2.80-3.09 (5H, m), 3.33-3.45 (1H, m), 3.69 (2H, dd,J=8.3, 5.7 Hz), 3.89-3.96 (4H, m), 4.14 (1H, t), 4.38 (1H, t, J=8.5 Hz),5.12 (2H, s), 5.55 (1H, s), 6.64 (1H, d, J=8.3 Hz), 7.08 (1H, d, J=1.5Hz), 7.17 (1H, dd, J=12.1, 1.5 Hz), 7.31-7.40 (6H, m), 9.77 (1H, s).

(Step 2)

A solution of benzyl(R)-2-(1-(5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)azetidin-3-yl)acetate(151 mg, 0.25 mmol) and 10% palladium-carbon (50 mg, 0.42 mmol, 50% wet)in MeOH (5 mL) was stirred under hydrogen atmosphere (1 atm) at roomtemperature for 3 hr. The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (Diol, solventgradient; 30→100% ethyl acetate/hexane) to give the title compound(109.3 mg, 0.214 mmol, 85%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.33 (6H, s), 1.90 (2H, t, J=7.4 Hz), 2.72(2H, d, J=7.6 Hz), 2.86 (2H, t, J=7.2 Hz), 2.89-3.08 (3H, m), 3.40-3.53(1H, m), 3.73 (2H, dd, J=8.5, 5.5 Hz), 3.88-3.98 (4H, m), 4.18 (1H, t),4.40 (1H, t, J=8.3 Hz), 5.57 (1H, s), 6.64 (1H, d, J=8.7 Hz), 7.10 (1H,s), 7.15 (1H, d, J=11.7 Hz), 7.39 (1H, d, J=8.7 Hz), 9.70 (1H, s).

[α]_(D) ²⁵ +85.9 (c 0.2525, MeOH)

Example 274(1-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)-3-hydroxyazetidin-3-yl)aceticacid (Step 1)

Benzyl acetate (2.78 mL, 19.28 mmol) was added to a solution of lithiumhexamethyldisilazane (14.83 mL, 19.28 mmol, 1.6M) in THF (20 mL) at −78°C., and the mixture was stirred at −78° C. for 30 min. To the reactionmixture was added tert-butyl 3-oxoazetidine-1-carboxylate (3 g, 17.52mmol), and the mixture was stirred overnight at room temperature. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 3→50% ethyl acetate/hexane) to givetert-butyl 3-(2-(benzyloxy)-2-oxoethyl)-3-hydroxyazetidine-1-carboxylate(3.38 g, 10.52 mmol, 60.0-) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 1.43 (9H, s), 2.87 (2H, s), 3.74 (1H, brs),3.77-3.85 (2H, m), 3.86-4.00 (2H, m), 5.18 (2H, s), 7.29-7.47 (5H, m).

(Step 2)

Sodium hydride (60% oil, 0.162 g, 4.05 mmol) was added to a solution oftert-butyl 3-(2-(benzyloxy)-2-oxoethyl)-3-hydroxyazetidine-1-carboxylate(1 g, 3.11 mmol) and benzyl bromide (0.389 mL, 3.27 mmol) in DMF (8 mL)at 0° C., and the mixture was stirred overnight at room temperature. Tothe reaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 5→50% ethyl acetate/hexane) to givetert-butyl3-(benzyloxy)-3-(2-(benzyloxy)-2-oxoethyl)azetidine-1-carboxylate (0.365g, 0.887 mmol, 28.5%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.44 (9H, s), 2.96 (2H, s), 3.93-4.18 (4H,m), 4.51 (2H, s), 5.14 (2H, s), 7.23-7.36 (10H, m).

(Step 3)

Cooled TFA (4 mL) was added to tert-butyl3-(benzyloxy)-3-(2-(benzyloxy)-2-oxoethyl)azetidine-1-carboxylate (365mg, 0.89 mmol) at 0° C., and the mixture was stirred at 0° C. for 20min. The reaction mixture was added to aqueous sodium hydrogen carbonatesolution, and the mixture was extracted with ethyl acetate. The organiclayer was dried over sodium sulfate, and the solvent was evaporatedunder reduced pressure to give benzyl2-(3-(benzyloxy)azetidin-3-yl)acetate (276 mg, 0.886 mmol, 100%) as apale orange oil.

MS(API): Calculated 311.4. Found 312.3 (M+H).

(Step 4)

The title compound was synthesized using benzyl2-(3-(benzyloxy)azetidin-3-yl)acetate and(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide,by the reaction and purification in the same manner as in Example 230and Example 231.

¹H NMR (300 MHz, DMSO-d₆): δ 0.29 (9H, s), 2.62 (2H, s), 2.70-2.84 (1H,m), 3.00-3.18 (1H, m), 3.34-3.42 (1H, m), 3.69-3.75 (4H, m), 3.76-3.96(3H, m), 4.14 (1H, d, J=8.3 Hz), 5.31 (1H, s), 5.71 (1H, brs), 6.70-6.87(2H, m), 7.20 (2H, d, J=9.8 Hz), 7.35-7.53 (1H, m), 10.66 (1H, s), 12.15(1H, brs).

Example 275(1-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)azetidin-3-yl)aceticacid (Step 1)

A solution of l-benzhydrylazetidin-3-one (0.8 g, 3.37 mmol) andtert-butyl triphenylphosphoranylideneacetate (1.269 g, 3.37 mmol) intoluene (10 mL) was stirred at 90° C. for 18 hr. The reaction mixturewas concentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (solvent gradient; 5→50%ethyl acetate/hexane) to give tert-butyl2-(1-benzhydrylazetidin-3-ylidene)acetate (0.880 g, 2.62 mmol, 78%) as apale yellow solid.

¹H NMR (300 MHz, CDCl₃): δ 1.42 (9H, s), 3.81-3.92 (2H, m), 4.09-4.18(2H, m), 4.52 (1H, s), 5.57 (1H, quin, J=2.3 Hz), 7.14-7.23 (2H, m),7.23-7.31 (4H, m), 7.37-7.46 (4H, m).

(Step 2)

A solution of tert-butyl 2-(1-benzhydrylazetidin-3-ylidene)acetate (880mg, 2.62 mmol) and 10% palladium-carbon (279 mg, 2.62 mmol, 50% wet) inMeOH (20 mL) was stirred overnight under hydrogen atmosphere (1 atm) atroom temperature. The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (solvent gradient;5→50% ethyl acetate/hexane) to give tert-butyl2-(1-benzhydrylazetidin-3-yl)acetate (830 mg, 2.460 mmol, 94%) as whitecrystals.

¹H NMR (300 MHz, CDCl₃): δ 1.35-1.42 (9H, m), 2.48 (2H, d, J=6.8 Hz),2.65-2.89 (3H, m), 3.27-3.27-3.47 (2H, m), 4.31 (1H, s), 7.08-7.20 (2H,m), 7.21-7.31 (4H, m), 7.33-7.46 (4H, m).

(Step 3)

A solution of tert-butyl 2-(1-benzhydrylazetidin-3-yl)acetate (830 mg,2.46 mmol) and 10% palladium hydroxide-carbon (200 mg, 1.88 mmol, 50%wet) in acetic acid (10 mL) was stirred under hydrogen atmosphere (1atm) at room temperature for 2 days. The catalyst was removed byfiltration, and the filtrate was concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(NH, solvent gradient; 5→100% ethyl acetate/hexane) to give tert-butyl2-(azetidin-3-yl)acetate (398 mg, 2.324 mmol, 94%) as a pale orange oil.

¹H NMR (300 MHz, CDCl₃): δ 1.43 (9H, s), 2.61 (2H, d, J=7.9 Hz), 3.16(1H, spt, J=7.9 Hz), 3.71 (2H, dd, J=10.8, 7.4 Hz), 3.99-4.10 (2H, m),5.20 (1H, brs).

(Step 4)

The title compound was synthesized using(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamideand tert-butyl 2-(azetidin-3-yl)acetate, by the reaction andpurification in the same manner as in Example 230 and Example 225.

¹H NMR (300 MHz, DMSO-d₆): δ 0.29 (9H, s), 2.38-2.44 (2H, m), 2.82 (2H,brs), 3.04 (2H, d, J=7.9 Hz), 3.27 (3H, s), 3.52 (2H, d, J=10.6 Hz),3.64-3.89 (2H, m), 4.12-4.20 (1H, m), 4.36 (3H, s), 5.38 (1H, s),6.99-7.33 (4H, m), 7.50 (1H, d, J=8.3 Hz), 10.74 (1H, s).

Example 2763-((((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)oxy)propanoicacid

The title compound was synthesized using(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamideand tert-butyl 3-hydroxypropanoate, by the reaction and purification inthe same manner as in Example 230 and Example 225.

¹H NMR (300 MHz, DMSO-d₆): δ 0.30 (9H, s), 2.44-2.60 (2H, m), 2.66-2.83(1H, m), 2.94-3.15 (1H, m), 3.39-3.50 (1H, m), 3.72 (3H, s), 3.79-4.00(1H, m), 4.19 (2H, d, J=17.4 Hz), 5.44 (1H, s), 6.80 (2H, s), 7.14-7.32(2H, m), 7.34-7.55 (1H, m), 10.70-10.91 (1H, m)

Example 2773-((((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)oxy)propanoicacid

The title compound was synthesized using(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamideand tert-butyl 3-hydroxypropanoate, by the reaction and purification inthe same manner as in Example 230 and Example 225.

¹H NMR (300 MHz, DMSO-d): δ 0.29 (9H, s), 1.29 (3H, t, J=7.0 Hz),2.24-2.43 (1H, m), 2.60-2.82 (1H, m), 2.90-3.13 (1H, m), 3.28-3.51 (2H,m), 3.98 (3H, d, J=7.2 Hz), 4.08-4.29 (2H, m), 5.27-5.50 (1H, m), 6.77(2H, brs), 7.14-7.34 (2H, m), 7.34-7.51 (1H, m), 10.86 (1H, s),11.10-11.38 (1H, m)

Example 278(1-(((5R)-2-(difluoromethoxy)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)azetidin-3-yl)aceticacid (Step 1)

(R)—N-(3,5-Difluoro-4-(trimethylsilyl)phenyl)-2-(difluoromethoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamidewas synthesized using6-(tert-butoxycarbonyl)-2-(difluoromethoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylicacid, by the reaction and purification in the same manner as in Steps 8to 10 of Example 254.

¹H NMR (300 MHz, CDCl₃): δ 0.33 (9H, t, J=1.5 Hz), 2.22 (1H, brs),2.75-2.98 (2H, m), 3.08-3.20 (1H, m), 3.22-3.33 (1H, m), 4.60 (1H, s),6.77 (1H, d, J=8.7 Hz), 7.05-7.13 (2H, m), 7.46 (1H, t), 7.98 (1H, d,J=8.7 Hz), 9.62 (1H, s).

(Step 2)

The title compound was synthesized using(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(difluoromethoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamideand benzyl 2-(azetidin-3-yl)acetate, by the reaction and purification inthe same manner as in Example 230 and Example 231.

¹H NMR (300 MHz, CDCl₃): δ 0.32 (9H, s), 2.71-2.77 (2H, m), 2.86-3.09(3H, m), 3.41-3.53 (1H, m), 3.74 (2H, dd, J=8.3, 5.7 Hz), 3.97 (1H, dd,J=8.5, 5.9 Hz), 4.19 (1H, t), 4.42 (1H, t, J=8.5 Hz), 5.63 (1H, s), 6.80(1H, d, J=8.3 Hz), 7.00-7.08 (2H, m), 7.45 (1H, dd), 7.53 (1H, d, J=8.7Hz), 10.06 (1H, s).

Example 279(1-(((1R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)azetidin-3-yl)aceticacid (Step 1)

Pyridine (0.152 mL, 1.88 mmol) was slowly added to a solution of benzyl2-(azetidin-3-yl)acetate (193 mg, 0.94 mmol) and bis(trichloromethyl)carbonate (279 mg, 0.94 mmol) in THF (5 mL) at 0° C., and the mixturewas stirred at 0° C. for 1 hr. The reaction mixture was concentratedunder reduced pressure. A solution of(R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(140 mg, 0.38 mmol) and DIEA (0.655 mL, 3.76 mmol) in DMF (5 mL) wasadded thereto at 0° C., and the mixture was stirred at room temperaturefor 2.5 hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with 10%aqueous citric acid solution, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 20→50%ethyl acetate/hexane) to give crude benzyl(R)-2-(1-(1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)azetidin-3-yl)acetate(160.7 mg, 0.266 mmol, 70.8%) as a white solid.

(Step 2)

A solution of benzyl(R)-2-(1-(1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)azetidin-3-yl)acetate(160.7 mg, 0.27 mmol) and 10% palladium-carbon (20 mg, 0.19 mmol, 50%wet) in MeOH (3.0 mL) was stirred under hydrogen atmosphere (1 atm) atroom temperature for 2 hr. The catalyst was removed by filtration, andthe filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 20→90% ethyl acetate/hexane) to give the title compound (94.3mg, 0.184 mmol, 69.0%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 0.24 (9H, s), 2.53-2.61 (2H, m), 2.69-2.85(2H, m), 2.99-3.13 (1H, m), 3.34-3.43 (1H, m), 3.47-3.58 (1H, m),3.66-3.75 (4H, m), 3.76-3.87 (1H, m), 3.90-3.99 (1H, m), 4.15 (1H, t,J=8.1 Hz), 5.34 (1H, s), 6.74-6.85 (2H, m), 7.23-7.37 (2H, m), 7.39-7.51(2H, m), 10.49 (1H, s), 12.24 (1H, brs)

[α]_(D) ²⁵ −7.9 (c 0.2525, MeOH)

Example 280(1-(((1R)-6-ethoxy-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)azetidin-3-yl)aceticacid

The title compound was synthesized using(R)-6-ethoxy-N-(3-fluoro-4-(trimethylsilyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamideand benzyl 2-(azetidin-3-yl)acetate, by the reaction and purification inthe same manner as in Example 230 and Example 231.

¹H NMR (300 MHz, DMSO-dr): δ 0.24 (9H, d, J=0.8 Hz), 1.29 (3H, t, J=7.0Hz), 2.53-2.60 (2H, m), 2.68-2.85 (2H, m), 2.98-3.13 (1H, m), 3.35-3.43(1H, m), 3.48-3.57 (1H, m), 3.67-3.75 (1H, m), 3.75-3.86 (1H, m),3.91-4.03 (3H, m), 4.15 (1H, t, J=8.3 Hz), 5.33 (1H, s), 6.71-6.83 (2H,m), 7.24-7.37 (2H, m), 7.38-7.53 (2H, m), 10.49 (1H, s), 12.19 (1H, brs)

[α]_(D) ²⁵ −11.6 (c 0.2515, MeOH)

Example 281(1-(((5R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)azetidin-3-yl)aceticacid (Step 1)

Pyridine (0.299 mL, 3.69 mmol) was slowly added to a solution of benzyl2-(azetidin-3-yl)acetate (379 mg, 1.85 mmol) and bis(trichloromethyl)carbonate (548 mg, 1.85 mmol) in THF (10 mL) at 0° C., and the mixturewas stirred at 0° C. for 1 hr. The reaction mixture was concentratedunder reduced pressure. A solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(289 mg, 0.74 mmol) and DIEA (1.286 mL, 7.38 mmol) in DMF (10 mL) wasadded thereto at 0° C., and the mixture was stirred at room temperaturefor 15 hr. To the reaction mixture was added water, and 2N hydrochloricacid was added thereto until the pH of the mixture became 3. The mixturewas extracted three times with ethyl acetate. The organic layer waswashed with aqueous sodium hydrogen carbonate solution and brine, anddried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 31→52% ethyl acetate/hexane), and thensilica gel column chromatography (NH, solvent gradient; 20→45% ethylacetate/hexane) to give benzyl(R)-2-(1-(5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)azetidin-3-yl)acetate(131 mg, 0.210 mmol, 28.5%) as a white solid.

MS(API): Calculated 622.7. Found 623.2 (M+H).

¹H NMR (300 MHz, CDCl₃): δ 0.32 (9H, t), 2.72 (2H, dd, J=7.7, 2.1 Hz),2.85-2.96 (2H, m), 2.97-3.08 (1H, m), 3.33-3.45 (1H, m), 3.64-3.73 (2H,m), 3.89-3.97 (4H, m), 4.10-4.19 (1H, m), 4.39 (1H, t, J=8.3 Hz), 5.13(2H, s), 5.55 (1H, s), 6.64 (1H, d, J=8.7 Hz), 7.01-7.10 (2H, m),7.29-7.40 (6H, m), 10.11 (1H, s).

(Step 2)

A solution of benzyl(R)-2-(1-(5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)azetidin-3-yl)acetate(128 mg, 0.21 mmol) and 10% palladium-carbon (45 mg, 0.38 mmol, 50% wet)in MeOH (4 mL) was stirred under hydrogen atmosphere (1 atm) at roomtemperature for 1.5 hr. The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (Diol, solventgradient; 30→100% ethyl acetate/hexane) to give the title compound (79.2mg, 0.149 mmol, 72.3%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 0.32 (9H, s), 2.70-2.76 (2H, m), 2.86-3.09(3H, m), 3.40-3.52 (1H, m), 3.74 (2H, dd, J=8.5, 5.9 Hz), 3.91 (3H, s),3.96 (1H, dd, J=8.5, 5.9 Hz), 4.19 (1H, t), 4.42 (1H, t, J=8.5 Hz), 5.57(1H, s), 6.65 (1H, d, J=8.3 Hz), 7.02-7.10 (2H, m), 7.37 (1H, d, J=8.7Hz), 10.03 (1H, s).

[α]_(D) ²⁵ +81.8 (c 0.2510, MeOH)

Example 2825-((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-oxopentanoicacid monosulfate dihydrate (Step 1)

Morpholine (261 mg, 261 μL, 2.99 mmol) and acetic acid (200 mg, 191 μL,3.32 mmol) were added to a solution of2,2-dimethyl-1,3-dioxane-4,6-dione (24.0 g, 166.17 mmol) in acetone (120g) under argon gas atmosphere at room temperature, and the mixture wasstirred at room temperature for 18 hr. The reaction mixture wasconcentrated under reduced pressure. To the obtained residue was addedsaturated aqueous sodium hydrogen carbonate solution (200 mL), and themixture was extracted with toluene (200 mL). The organic layer waswashed with 10% brine (200 mL), and the solvent was evaporated underreduced pressure to give5-isopropylidene-2,2-dimethyl-1,3-dioxane-4,6-dione as a white solid.

¹H NMR (500 MHz, CDCl₃): δ1.72 (6H, s), 2.52 (6H, s).

1M Isopropylmagnesium chloride THF solution (183 mL, 182.79 mmol) wasadded dropwise to a solution of 4-bromo-2-fluoro-1-iodobenzene (50.0 g,166.17 mmol) in anhydrous THF (96 mL) over 20 min at −20° C. under argongas atmosphere. The reaction mixture was stirred at −20° C. for 30 min,and added dropwise to a solution of5-isopropylidene-2,2-dimethyl-1,3-dioxane-4,6-dione in anhydrous toluene(84 mL) at −20° C. over 20 min, and the container was washed with THF(24 mL). The reaction mixture was stirred at 0° C. for 3 hr, 10% aqueouscitric acid solution (200 mL) was added thereto at 0° C., and themixture was extracted with toluene (200 mL). The organic layer wasconcentrated under reduced pressure to give5-(2-(4-bromo-2-fluorophenyl)propan-2-yl)-2,2-dimethyl-1,3-dioxane-4,6-dioneas a pale yellow oil.

4M Hydrochloric acid (96 mL) was added to a solution of5-(2-(4-bromo-2-fluorophenyl)propan-2-yl)-2,2-dimethyl-1,3-dioxane-4,6-dionein DMF (60 mL), and the mixture was stirred at 100° C. for 24 hr. Thereaction mixture was concentrated under reduced pressure at 75° C., andthe pH of the obtained residue was adjusted to 9.0 with 8M aqueoussodium hydroxide solution (50 mL). The mixture was stirred at 0° C. for10 min, and filtered, and the insoluble substance was washed with water(100 mL). The pH of the filtrate was adjusted to 4.0 with 6Mhydrochloric acid (20 mL) at 0° C., and the mixture was stirred at 0° C.for 1 hr. The precipitate was collected by filtration, washed with icewater, and dried at 50° C. to give3-(4-bromo-2-fluorophenyl)-3-methylbutanoic acid (24.52 g, 85.49 mmol,51%) as white crystals.

¹H NMR (500 MHz, CDCl₃): δ1.46 (6H, s), 2.80 (2H, s), 7.13-7.22 (3H, m)(The peak derived from COOH was not observed).

(Step 2)

A mixture of 3-(4-bromo-2-fluorophenyl)-3-methylbutanoic acid (20.0 g,72.70 mmol) and PPA (200 g) was stirred at 100° C. for 4 hr. To thereaction mixture was added ice water (200 mL) at 0° C., and the mixturewas extracted twice with ethyl acetate (200 mL). The organic layer waswashed with saturated aqueous sodium hydrogen carbonate solution (200mL), 8M aqueous sodium hydroxide solution (35 mL) and 10% brine, andconcentrated under reduced pressure. To a mixture of the obtainedresidue in a mixed solvent of DMF (140 mL) and EtOH (140 mL) was addedwater (240 mL) at room temperature, and the mixture was stirred at 0° C.for 2 hr. The precipitate was collected by filtration, washed with water(100 mL), and dried at 50° C. to give6-bromo-4-fluoro-3,3-dimethylindan-1-one (17.0 g, 66.12 mmol, 91%) aspale orange crystals.

¹H NMR (500 MHz, CDCl₃): δ1.52 (6H, s), 2.63 (2H, s), 7.41 (1H, dd,J=9.0, 1.7 Hz), 7.65 (1H, d, J=1.6 Hz).

(Step 3)

Triethylsilane (1.59 g, 2.17 mL, 13.63 mmol) was added to a solution of6-bromo-4-fluoro-3,3-dimethylindan-1-one (1.5 g, 5.83 mmol) in TFA (30mL) at room temperature, and the mixture was stirred at room temperaturefor 40 hr. To the reaction mixture was added ice water at 0° C., and themixture was extracted twice with ethyl acetate. The organic layer waswashed with aqueous sodium hydroxide solution (the pH of the aqueouslayer was adjusted to 7.0) and 10% brine, and concentrated under reducedpressure to give crude 5-bromo-7-fluoro-1,1-dimethylindane as an orangeoil.

¹H NMR (500 MHz, CDCl₃): δ1.35 (6H, s), 1.93 (2H, t, J=7.3 Hz), 2.90(2H, t, J=7.4 Hz), 6.98 (1H, dt, J=9.5, 0.8 Hz), 7.06-7.13 (1H, m).

Pd₂(dba)₃ (267 mg, 0.29 mmol), BINAP (363 mg, 0.58 mmol), sodiumtert-butoxide (841 mg, 8.75 mmol) and benzphenone imine (1.05 g, 0.98mL, 5.83 mmol) were added to a solution of the crude5-bromo-7-fluoro-1,1-dimethylindane in anhydrous toluene (30 mL) underargon gas atmosphere at room temperature, and the mixture was stirred at80° C. for 1 hr. To the reaction mixture was added water, and themixture was extracted twice with ethyl acetate. The organic layer wasconcentrated under reduced pressure to give crudeN-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-1,1-diphenylmethanimineas an orange oil.

To a solution of the crudeN-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-1,1-diphenylmethaniminein THF (30 mL) was added IM hydrochloric acid (29 mL, 29.17 mmol) atroom temperature, and the mixture was stirred at room temperature for 30min. To the reaction mixture was added sodium hydroxide until the pH ofthe reaction mixture became >7, and the mixture was extracted twice withethyl acetate. The organic layer was washed with 10% brine, andconcentrated under reduced pressure to give crude7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine as an orange oil.

¹H NMR (500 MHz, CDCl₃): δ1.33 (6H, s), 1.88 (2H, t, J=7.4 Hz), 2.81(2H, t, J=7.4 Hz), 3.60 (2H, s), 6.15-6.17 (1H, m), 6.28-6.29 (1H, m).

A solution of (+)-camphorsulfonic acid (1.49 g, 6.42 mmol) in ethylacetate (37.5 mL) was added to the crude7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine in ethyl acetate (15mL) at room temperature, and the container was washed with ethyl acetate(7.5 mL). The mixture was stirred at 0° C. for 2 hr. The precipitate wascollected by filtration, washed with ethyl acetate, and dried at 40° C.to give 7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine(+)-camphorsulfonate (1.38 g, 3.36 mmol, 58%) as pale yellow crystals.

¹H NMR (500 MHz, CDCl₃): δ0.74 (3H, s), 0.93 (3H, s), 1.22-1.30 (1H, m),1.34 (6H, s), 1.52-1.60 (1H, m), 1.77-1.90 (2H, m), 1.93 (2H, t, J=7.4Hz), 1.96-2.00 (1H, m), 2.23-2.30 (1H, m), 2.35-2.44 (1H, m), 2.74 (1H,d, J=14.8 Hz), 2.91 (2H, t, J=7.4 Hz), 3.31 (1H, d, J=14.5 Hz),7.05-7.10 (1H, m), 7.15-7.20 (1H, m), 8.58-10.43 (2H, br) (Theexchangeable 1H was not observed).

(Step 4)

1.6 M n-Butyllithium/hexane solution (282 mL, 451.96 mmol) was addeddropwise to a solution of 2-methoxy-6-methylpyridine (50.60 g, 410.87mmol) in THF (625 mL) over 1 hr under argon gas atmosphere at −78° C.The reaction mixture was stirred at −78° C. for 45 min, paraformaldehyde(49.3 g, 1643.49 mmol) was added thereto at −78° C., and the mixture wasvigorously stirred at room temperature for 3.5 hr. The reaction mixturewas poured into ice water (1000 mL), and the mixture was saturated withsodium chloride, and extracted three times with a mixed solvent of ethylacetate/THF (3:1). The organic layer was washed with water and brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 8→50% ethyl acetate/hexane) to give2-(6-methoxypyridin-2-yl)ethanol (23.22 g, 152 mmol, 37%) as a colorlessoil.

¹H NMR (300 MHz, CDCl₃): δ 2.94 (2H, t, J=5.5 Hz), 3.91 (3H, s), 4.00(2H, q, J=4.5 Hz), 4.30 (1H, t, J=5.9 Hz), 6.62 (1H, d, J=8.3 Hz), 6.73(1H, d, J=7.2 Hz), 7.51 (1H, dd, J=8.3, 7.2 Hz).

(Step 5)

ADDP (49.0 g, 194.09 mmol) was added to a mixture of2-(6-methoxypyridin-2-yl)ethanol (22.87 g, 149.30 mmol), phthalimide(24.16 g, 164.23 mmol), tributylphosphine (48.5 mL, 194.09 mmol) and THF(340 mL) under argon gas atmosphere at 0° C., the obtain solution wasstirred at room temperature for 16 hr. To the reaction mixture was addedethyl acetate (about 500 mL), and the mixture was stirred at 0° C. for20 min. The insoluble substance was removed by filtration with ethylacetate, and washed with ethyl acetate. The filtrate was added to water(1000 mL), and the mixture was extracted three times with ethyl acetate.The organic layer was washed with water and brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 5→20% ethyl acetate/hexane), and theprecipitate was collected by filtration with hexane to give2-(2-(6-methoxypyridin-2-yl)ethyl)isoindoline-1,3-dione (29.03 g, 103mmol, 69%) as a grayish white powder.

¹H NMR (300 MHz, CDCl₃): δ 3.08 (2H, t, J=7.2 Hz), 3.78 (3H, s), 4.11(2H, t, J=7.2 Hz), 6.54 (1H, d, J=7.9 Hz), 6.72 (1H, d, J=7.2 Hz), 7.43(1H, dd, J=8.3, 7.2 Hz), 7.70 (2H, dd, J=5.5, 3.2 Hz), 7.82 (2H, dd,J=6.3, 3.0 Hz).

(Step 6)

Hydrazine monohydrate (24.94 mL, 514.18 mmol) was added to a solution of2-(2-(6-methoxypyridin-2-yl)ethyl)isoindoline-1,3-dione (29.03 g, 102.84mmol) in EtOH (300 mL) at room temperature. The mixture was heated underreflux for 1 hr, and cooled to room temperature. The insoluble substancewas removed by filtration, and washed with a mixed solvent of diethylether/IPE (1:1). The filtrate was concentrated under reduced pressure.To the obtained residue was added toluene (about 250 mL), and themixture was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (NH, solvent gradient;10→100% ethyl acetate/hexane) to give2-(6-methoxypyridin-2-yl)ethanamine (14.43 g, 95 mmol, 92%) as acolorless oil.

¹H NMR (300 MHz, CDCl₃): δ 1.31 (2H, brs), 2.82 (2H, t, J=7.5 Hz), 3.11(2H, t, J=6.0 Hz), 3.92 (3H, s), 6.57 (1H, d, J=7.9 Hz), 6.73 (1H, d,J=7.2 Hz), 7.48 (1H, dd, J=8.1, 7.4 Hz).

(Step 7)

1.6 M n-Butyllithium/hexane solution (300 mL, 479.43 mmol) was added toa solution of acetonitrile (21.87 g, 532.70 mmol) in THF (630 mL) underargon gas atmosphere at −78° C., and the mixture was stirred at −78° C.for 30 min. 2-Bromo-6-methoxypyridine (25.04 g, 133.18 mmol) was addeddropwise thereto at −78° C. over 15 min, and the reaction mixture wasstirred at room temperature for 4 hr. The reaction mixture was pouredinto ice water (900 mL), and the mixture was extracted three times withethyl acetate. The organic layer was washed with water and brine, anddried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 2→20% ethyl acetate/hexane) to give2-(6-methoxypyridin-2-yl)acetonitrile (11.37 g, 77 mmol, 58%) as acolorless oil.

¹H NMR (300 MHz, CDCl₃): δ 3.81 (2H, s), 3.93 (3H, s), 6.69 (1H, d,J=8.3 Hz), 6.93-6.98 (1H, m), 7.58 (1H, dd, J=8.3, 7.6 Hz).

(Step 8)

In the presence of Raney nickel (8 g, 136.30 mmol) [prepared by washingKawaken NDHT-90 with 4N aqueous sodium hydroxide solution (40 m, 5 min),water (five times) and MeOH (three times)], a solution of2-(6-methoxypyridin-2-yl)acetonitrile (5.00 g, 33.75 mmol) in 2Mammonia/MeOH (84 mL, 168.73 mmol) was stirred under hydrogen atmosphere(0.5 MPa) at room temperature for 22 hr. The catalyst was removed bydecantation, and the reaction solution was concentrated under reducedpressure. To the obtained residue was added toluene (about 80 mL), andthe mixture was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (NH, solventgradient; 10→100% ethyl acetate/hexane) to give2-(6-methoxypyridin-2-yl)ethanamine (4.30 g, 28.3 mmol, 84%) as a yellowoil.

(Step 9)

A solution of 2-(6-methoxypyridin-2-yl)ethanamine (14.43 g, 94.81 mmol),4N hydrogen chloride/CPME (26.1 mL, 104.29 mmol) and 47% ethylglyoxylate/toluene solution (polymer form) (30.0 mL, 142.22 mmol) inEtOH (175 mL) was heated under reflux for 8 hr. To the reaction mixturewere added 4N hydrogen chloride/CPME (26.1 mL, 104.29 mmol) and 47%ethyl glyoxylate/toluene solution (polymer form) (30.0 mL, 142.22 mmol),and the mixture was heated under reflux for additional 16 hr. Thereaction mixture was concentrated under reduced pressure to half volume,and to the residue was added diethyl ether (ca. 150 mL). The precipitatewas collected by filtration, and washed with EtOH/diethyl ether to givecrude ethyl 2-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylatehydrochloride (20.01 g, 77 mmol, 82%) as a grayish white powder.

¹H NMR (300 MHz, DMSO-d₆): δ 1.25 (3H, t, J=7.0 Hz), 2.71-2.93 (2H, m),3.37-3.51 (2H, m), 4.19-4.31 (2H, m), 5.23 (1H, s), 6.30 (1H, d, J=9.4Hz), 7.43 (1H, d, J=9.4 Hz), 8.12 (1H, brs), 9.65 (1H, brs), 10.56 (1H,brs).

(Step 10)

Boc₂O (17.72 g, 81.22 mmol) was added to a mixture of ethyl2-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylatehydrochloride (20.01 g, 77.35 mmol), TEA (11.32 mL, 81.22 mmol), THF(205 mL) and water (75 mL) at room temperature, and the mixture wasvigorously stirred at room temperature for 5.5 hr. The reaction mixturewas poured into water (500 mL), and the mixture was saturated withsodium chloride, and extracted three times with a mixed solvent of ethylacetate/THF (3:1). The organic layer was washed with water and brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The precipitate was collected by filtration, andwashed with IPE/hexane to give 5-ethyl 6-tert-butyl2-hydroxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (16.57 g,51.4 mmol, 66%) as a white powder.

¹H NMR (300 MHz, CDCl₃)d 1.24-1.32 (3H, m), 1.45-1.50 (9H, m), 2.66-2.92(2H, m), 3.37-3.55 (1H, m), 4.10-4.29 (3H, m), 5.18-5.43 (1H, m), 6.46(1H, d, J=9.4 Hz), 7.58-7.66 (1H, m), 12.94 (1H, brs).

(Step 11)

Iodomethane (8.69 mL, 139.60 mmol) was added to a mixture of 5-ethyl6-tert-butyl2-hydroxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (7.50 g,23.27 mmol), silver(I) carbonate (8.34 g, 30.25 mmol) and THF (150 mL)at room temperature (the reaction container was light-blocked). Themixture was stirred at room temperature for 15 hr, and then at 50° C.for 5 hr. The insoluble substance was removed by filtration throughCelite, and washed with ethyl acetate. The filtrate was concentratedunder reduced pressure, and the obtained residue was purified by silicagel column chromatography (solvent gradient; 5→30% ethyl acetate/hexane)to give 5-ethyl 6-tert-butyl2-methoxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (6.93 g,20.60 mmol, 89%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 1.21-1.30 (3H, m), 1.44-1.53 (9H, m),2.84-2.96 (2H, m), 3.55-3.70 (1H, m), 3.91 (3H, s), 4.01-4.22 (3H, m),5.33-5.54 (1H, m), 6.60 (1H, d, J=8.7 Hz), 7.69 (1H, t, J=7.5 Hz).

(Step 12)

Trimethyloxonium tetrafluoroborate (1.775 g, 12.00 mmol) was added to amixture of 5-ethyl 6-tert-butyl2-hydroxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (1.289 g,4.00 mmol) and acetonitrile (18 mL) at 0° C. The mixture was stirred at0° C. for 2 hr, the reaction mixture was poured into ice-cooledsaturated aqueous sodium hydrogen carbonate solution (100 mL), and themixture was extracted three times with ethyl acetate. The organic layerwas washed with water and brine, and dried over magnesium sulfate, andthe solvent was evaporated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (solvent gradient;2→19% ethyl acetate/hexane) to give 5-ethyl 6-tert-butyl2-methoxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (372 mg,1.106 mmol, 28%) as a colorless oil.

(Step 13)

2N Lithium hydroxide (61.8 mL, 123.61 mmol) was added to a solution of5-ethyl 6-tert-butyl2-methoxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (6.93 g,20.60 mmol) in a mixed solvent of EtOH (30 mL) and THF (30 mL) at roomtemperature, and the mixture was stirred at room temperature for 1.5 hr.The reaction mixture was poured into ice-cooled water, and 6Nhydrochloric acid was added thereto until the pH of the mixture became4. Then, the mixture was extracted three times with a mixed solvent ofethyl acetate/THF (3:1). The organic layer was washed with water andbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure to give6-(tert-butoxycarbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylicacid (6.37 g, 20.66 mmol, 100%) as a colorless amorphous solid.

¹H NMR (300 MHz, CDCl₃): δ 1.44-1.52 (9H, m), 2.85-2.95 (2H, m),3.57-3.68 (1H, m), 3.90 (3H, s), 3.97-4.07 (1H, m), 5.36-5.57 (1H, m),6.61 (1H, d, J=8.3 Hz), 7.68 (1H, d, J=8.7 Hz). (The exchangeable 1H wasnot observed)

(Step 14)

T3P (4.89 mL, 8.22 mmol) was added to a solution of6-(tert-butoxycarbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylicacid (1.69 g, 5.48 mmol),7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine (0.982 g, 5.48 mmol),DIEA (4.77 mL, 27.41 mmol) and DMAP (0.737 g, 6.03 mmol) in ethylacetate (40 mL) at room temperature. The mixture was stirred at 65° C.for 15 hr, the reaction mixture was poured into water (150 mL), and themixture was extracted three times with ethyl acetate. The organic layerwas washed with 10% aqueous citric acid solution, aqueous sodiumhydrogen carbonate solution and brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedprecipitate was washed with hexane to give tert-butyl5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(2.09 g, 4.45 mmol, 81%) as a grayish white powder.

¹H NMR (300 MHz, CDCl₃): δ 1.34 (6H, s), 1.53 (9H, s), 1.91 (2H, t,J=7.4 Hz), 2.83-3.01 (4H, m), 3.45 (1H, brs), 3.91 (3H, s), 4.06 (1H,dt, J=13.2, 4.9 Hz), 5.56 (1H, brs), 6.64 (1H, d, J=8.3 Hz), 7.05-7.12(2H, m), 7.48 (1H, brs), 8.70 (1H, brs).

(Step 15)

tert-Butyl5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(2.09 g) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give tert-butyl(R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(960 mg, >99% ee), and the fraction having a longer retention time wasconcentrated to give tert-butyl(S)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(920 mg, >99% ee), each as a grayish white amorphous solid.

purification condition by chiral column chromatography

column: CHIRALPAK IA (QK001) 50 mmID×500 mmL

solvent: hexane/EtOH=900/100

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 16)

TFA (13 mL) was added to tert-butyl(R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(957 mg, 2.04 mmol) at room temperature, and the mixture was stirred atroom temperature for 20 min. The reaction mixture was added toice-cooled saturated aqueous sodium hydrogen carbonate solution (110mL), and potassium carbonate was added thereto until the pH of themixture became 8. Then, the mixture was extracted three times with ethylacetate. The organic layer was washed with water and brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure to give(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(732 mg, 1.981 mmol, 97%) as a grayish white amorphous solid.

¹H NMR (300 MHz, CDCl₃): δ 1.34 (6H, s), 1.69 (1H, brs), 1.91 (2H, t,J=7.4 Hz), 2.73-2.98 (4H, m), 3.12-3.28 (2H, m), 3.90 (3H, s), 4.57 (1H,s), 6.60 (1H, d, J=8.7 Hz), 7.11-7.17 (2H, m), 7.84 (1H, d, J=8.7 Hz),9.41 (1H, s).

(Step 17)

Dihydro-2H-pyran-2,6(3H)-dione (2.405 g, 21.08 mmol) was added to asolution of(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide(5.99 g, 16.21 mmol) and TEA (3.39 mL, 24.32 mmol) in THF (140 mL) atroom temperature, and the mixture was stirred at room temperature for 15hr. The reaction mixture was poured into water (600 mL), and 2Nhydrochloric acid was added thereto until the pH of the mixture became4. Then, the mixture was extracted three times with ethyl acetate. Theorganic layer was washed with water and brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified twice by silica gel column chromatography(Diol, solvent gradient; 30→100% ethyl acetate/hexane) to give5-((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-oxopentanoicacid (7.77 g, 16.07 mmol, 99%) as a colorless amorphous solid. Theobtained solid (4.50 g) was dissolved in ethyl acetate (16 mL) at 75°C., and heptane (25 mL) was added thereto. Seed crystals were addedthereto, the mixture was treated with ultrasonic wave, and theprecipitated crystals were washed with heptane to give colorless prismcrystals (3.87 g).

Elemental Analysis: C₂₆H₃₀N₃O₅F

Calculated C, 64.58; H, 6.25; N, 8.69.

Found C, 64.74; H, 6.66; N, 8.27.

(Step 18)

0.126 M Sulfuric acid (6.89 mL, 0.87 mmol, THF solution) was added to asolution of5-((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-oxopentanoicacid (400 mg, 0.83 mmol) in THF (10 mL) at room temperature, and themixture was stirred at room temperature for 30 min. The reaction mixturewas concentrated under reduced pressure to dryness, and to the obtainedresidue were added water (0.075 mL, 4.14 mmol) and toluene (17 mL). Seedcrystals were added thereto, and the mixture was slowly cooled, andstirred at 0° C. for 6 days. The precipitated crystals were collected byfiltration, and washed with diethyl ether to give the title compound(332.8 mg, 0.539 mmol, 65%) as white crystals.

¹H NMR (300 MHz, DMSO-d): δ 1.29 (6H, s), 1.75 (2H, quin, J=7.1 Hz),1.87 (2H, t, J=7.4 Hz), 2.28 (2H, t, J=7.5 Hz), 2.41-2.48 (1H, m),2.53-2.63 (1H, m), 2.82-2.95 (3H, m), 3.04 (1H, dt, J=18.0, 4.5 Hz),3.79-3.89 (4H, m), 4.04 (1H, ddd, J=12.7, 8.0, 4.5 Hz), 5.74 (1H, s),6.74 (1H, d, J=8.7 Hz), 7.18 (1H, s), 7.23 (1H, d, J=12.8 Hz), 7.80 (1H,d, J=8.7 Hz), 7.90 (3H, brs), 10.48 (1H, s). (4H derived from water wasnot observed)

Elemental Analysis: C₂₆H₃₃FN₃O₅.H₂SO₄.2H₂O

Calculated C, 50.56; H, 5.87; N, 6.80.

Found C, 50.33; H, 5.86; N, 6.69.

crystallinity: 61%

[α]_(D) ²⁵ +81.1 (c 0.2510, MeOH)

Example 283(1-(((1R)-6-(difluoromethoxy)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)azetidin-3-yl)aceticacid

The title compound was synthesized using(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-(difluoromethoxy)-1,2,3,4-tetrahydroisoquinoline-1-carboxamideand benzyl 2-(azetidin-3-yl)acetate, by the reaction and purification inthe same manner as in Example 230 and Example 231.

¹H NMR (300 MHz, CDCl₃): δ 0.31 (9H, s), 2.70-2.77 (2H, m), 2.85-3.08(3H, m), 3.57 (2H, dd, J=7.0, 5.1 Hz), 3.73 (1H, dd, J=8.5, 5.9 Hz),3.96 (1H, dd, J=8.5, 5.9 Hz), 4.19 (1H, t), 4.40 (1H, t, J=8.5 Hz), 5.66(1H, s), 6.50 (1H, t), 6.95-7.07 (4H, m), 7.24 (1H, d), 10.06 (1H, s).

[α]_(D) ²⁵ +7.4 (c 0.2515, MeOH)

Example 2845-((6R)-6-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,6,8,9-tetrahydrofuro[2,3-f]isoquinolin-7(2H)-yl)-5-oxopentanoicacid

The title compound was synthesized using(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2,3,6,7,8,9-hexahydrofuro[2,3-f]isoquinoline-6-carboxamide,by the reaction and purification in the same manner as in Step 9 ofExample 252.

¹H NMR (300 MHz, CDCl₃): δ 1.30 (6H, s), 1.86 (2H, t, J=7.4 Hz), 2.06(2H, quin, J=7.1 Hz), 2.48 (2H, t, J=6.8 Hz), 2.61 (2H, td, J=7.1, 2.5Hz), 2.77-2.90 (3H, m), 2.97 (1H, dt), 3.20 (2H, t, J=8.7 Hz), 3.77-3.83(2H, m), 4.59 (2H, t, J=8.9 Hz), 6.03 (1H, s), 6.82 (1H, d, J=7.6 Hz),6.98 (1H, s), 7.05-7.14 (2H, m), 9.05 (1H, s).

Example 2855-((7R)-7-((7-fluoro-1,1-dimethyl-2,3-dihydro-H-inden-5-yl)carbamoyl)-2,3,9,10-tetrahydro[1,4]dioxino[2,3-f]isoquinolin-8(7H)-yl)-5-oxopentanoicacid (Step 1)

A solution of 2,3-dihydroxybenzaldehyde (10.00 g, 72.40 mmol),1,2-dibromoethane (18.72 mL, 217.20 mmol) and potassium carbonate (30.0g, 217.20 mmol) in DMF (200 mL) was stirred at 70° C. for 15 hr. Thereaction mixture was cooled, water was added thereto, and the mixturewas extracted three times with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The precipitate was collected byfiltration with cooled hexane to give2,3-dihydrobenzo[b][1,4]dioxin-5-carbaldehyde (10.86 g, 66.2 mmol, 91%)as pale yellow crystals.

¹H NMR (300 MHz, CDCl₃): δ 4.30-4.35 (2H, m), 4.37-4.42 (2H, m), 6.91(1H, td), 7.10 (1H, dd, J=8.1, 1.7 Hz), 7.40 (1H, dd, J=7.7, 1.7 Hz),10.37 (1H, s).

(Step 2)

8-(tert-Butoxycarbonyl)-2,3,7,8,9,10-hexahydro-[1,4]dioxino[2,3-f]isoquinoline-7-carboxylicacid was synthesized using2,3-dihydrobenzo[b][1,4]dioxin-5-carbaldehyde, by the reaction andpurification in the same manner as in Steps 1 to 7 of Example 254.

¹H NMR (300 MHz, CDCl₃): δ 1.47 (9H, d, J=11.3 Hz), 2.79 (2H, t),3.61-3.80 (2H, m), 4.20-4.30 (4H, m), 5.33-5.54 (1H, m), 6.75 (1H, d,J=8.7 Hz), 6.97 (1H, d, J=8.7 Hz).

(Step 3)

(R)—N-(7-Fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2,3,7,8,9,10-hexahydro-[1,4]dioxino[2,3-f]isoquinoline-7-carboxamidewas synthesized using8-(tert-butoxycarbonyl)-2,3,7,8,9,10-hexahydro-[1,4]dioxino[2,3-f]isoquinoline-7-carboxylicacid and 7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-aminehydrochloride, by the reaction and purification in the same manner as inSteps 8 to 10 of Example 254.

¹H NMR (300 MHz, CDCl₃): δ 1.33 (6H, s), 1.90 (2H, t, J=7.6 Hz), 2.05(1H, brs), 2.69 (2H, t, J=5.9 Hz), 2.86 (2H, t, J=7.4 Hz), 3.10 (2H, t),4.20-4.30 (4H, m), 4.58 (1H, s), 6.75 (1H, d, J=8.7 Hz), 7.07 (1H, d,J=8.7 Hz), 7.11-7.18 (2H, m), 9.20 (1H, s).

(Step 4)

The title compound was synthesized using(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2,3,7,8,9,10-hexahydro-[1,4]dioxino[2,3-f]isoquinoline-7-carboxamide,by the reaction and purification in the same manner as in Step 9 ofExample 252.

¹H NMR (300 MHz, CDCl₃): δ 1.30 (6H, s), 1.86 (2H, t, J=7.4 Hz),2.01-2.12 (3H, m), 2.48 (2H, t, J=6.6 Hz), 2.54-2.68 (2H, m), 2.81 (2H,t, J=7.4 Hz), 2.85-2.92 (1H, m), 2.98 (1H, dt), 3.73-3.84 (2H, m),4.21-4.31 (4H, m), 5.96 (1H, s), 6.77 (1H, d), 6.83 (1H, d), 6.97 (1H,s), 7.09 (1H, dd, J=11.9, 1.7 Hz), 9.10 (1H, s).

Example 2865-((6R)-6-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,6,8,9-tetrahydrofuro[2,3-f]isoquinolin-7(2H)-yl)-5-oxopentanoicacid (Step 1)

1M Borane-THF complex THF solution (193 mL, 193.35 mmol) was slowlyadded to a solution of 2,3-dihydrobenzofuran-7-carboxylic acid (10.58 g,64.45 mmol) in THF (65 mL) over 30 min while the reaction solution wasmaintained at room temperature. The reaction mixture was stirred at 60°C. for 3.5 hr, and poured into ice (about 400 g). The mixture wasstirred at room temperature for 30 min, and extracted three times withethyl acetate. The organic layer was washed with aqueous sodium hydrogencarbonate solution and brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure to give(2,3-dihydrobenzofuran-7-yl)methanol (9.76 g, 65.0 mmol, quant.) as acolorless oil.

¹H NMR (300 MHz, CDCl₃): δ 2.08 (1H, brs), 3.22 (2H, t, J=8.9 Hz), 4.61(2H, t, J=8.7 Hz), 4.67 (2H, s), 6.83 (1H, t), 7.08 (1H, d, J=7.6 Hz),7.15 (1H, dd, J=7.4, 0.9 Hz).

(Step 2)

A mixture of (2,3-dihydrobenzofuran-7-yl)methanol (9.76 g, 64.99 mmol)and manganese dioxide (45.2 g, 519.93 mmol) in toluene (250 mL) wasstirred at 60° C. for 3 hr. The manganese dioxide was filtered off, andthe filtrate was concentrated under reduced pressure. The precipitatewas collected by filtration and washed with cooled hexane to give2,3-dihydrobenzofuran-7-carbaldehyde (7.43 g, 50.1 mmol, 77%) as a paleyellow solid.

¹H NMR (300 MHz, CDCl₃): δ 3.25 (2H, t, J=8.7 Hz), 4.74 (2H, t, J=8.7Hz), 6.93 (1H, t, J=7.6 Hz), 7.41 (1H, dq, J=7.2, 1.3 Hz), 7.58 (1H, dd,J=7.9, 0.8 Hz), 10.20 (1H, s).

(Step 3)

7-(tert-Butoxycarbonyl)-2,3,6,7,8,9-hexahydrofuro[2,3-f]isoquinoline-6-carboxylicacid was synthesized using 2,3-dihydrobenzofuran-7-carbaldehyde, by thereaction and purification in the same manner as in Steps 1 to 7 ofExample 254.

¹H NMR (300 MHz, CDCl₃): δ 1.43-1.50 (9H, m), 2.73-2.83 (2H, m), 3.20(2H, t, J=8.7 Hz), 3.62-3.82 (2H, m), 4.58 (2H, t, J=9.1 Hz), 5.39-5.61(1H, m), 6.98 (1H, d), 7.05 (1H, d).

(Step 4)

(R)—N-(7-Fluoro-1,1-dimethyl-2,3-dihydro-H-inden-5-yl)-2,3,6,7,8,9-hexahydrofuro[2,3-f]isoquinoline-6-carboxamidewas synthesized using7-(tert-butoxycarbonyl)-2,3,6,7,8,9-hexahydrofuro[2,3-f]isoquinoline-6-carboxylicacid, by the reaction and purification in the same manner as in Steps 8to 10 of Example 254.

¹H NMR (300 MHz, CDCl₃): δ 1.33 (6H, s), 1.90 (2H, t, J=7.4 Hz), 2.05(1H, brs), 2.63-2.77 (2H, m), 2.86 (2H, t, J=7.4 Hz), 3.12 (2H, t), 3.19(2H, t, J=8.7 Hz), 4.57 (2H, t, J=8.7 Hz), 4.63 (1H, s), 7.02-7.18 (4H,m), 9.18 (1H, s).

(Step 5)

The title compound was synthesized using(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2,3,6,7,8,9-hexahydrofuro[2,3-f]isoquinoline-6-carboxamide,by the reaction and purification in the same manner as in Step 9 ofExample 252.

¹H NMR (300 MHz, CDCl₃): δ 0.28 (9H, t, J=1.3 Hz), 2.12 (2H, quin, J=6.5Hz), 2.43-2.65 (3H, m), 2.77-2.97 (2H, m), 3.01-3.12 (1H, m), 3.20 (2H,t, J=8.7 Hz), 3.75 (1H, ddd, J=12.3, 7.6, 4.7 Hz), 3.98 (1H, ddd,J=12.2, 7.1, 4.5 Hz), 4.58 (2H, t, J=8.7 Hz), 5.91 (1H, s), 6.81-6.89(2H, m), 6.98 (1H, d), 7.07 (1H, d), 9.70 (1H, s).

Example 2875-((7R)-7-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2,3,9,10-tetrahydro[1,4]dioxino[2,3-f]isoquinolin-8(7H)-yl)-5-oxopentanoicacid (Step 1)

(R)—N-(3,5-Difluoro-4-(trimethylsilyl)phenyl)-2,3,7,8,9,10-hexahydro-[1,4]dioxino[2,3-f]isoquinoline-7-carboxamidewas synthesized using8-(tert-butoxycarbonyl)-2,3,7,8,9,10-hexahydro-[1,4]dioxino[2,3-f]isoquinoline-7-carboxylicacid and 3,5-difluoro-4-(trimethylsilyl)aniline, by the reaction andpurification in the same manner as in Steps 8 to 10 of Example 254.

¹H NMR (300 MHz, CDCl₃): δ 0.32 (9H, t, J=1.3 Hz), 1.61 (1H, brs), 2.69(2H, t, J=5.9 Hz), 3.03-3.18 (2H, m), 4.20-4.31 (4H, m), 4.59 (1H, s),6.76 (1H, d, J=8.3 Hz), 7.03-7.13 (3H, m), 9.42 (1H, s).

(Step 2)

The title compound was synthesized using(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2,3,7,8,9,10-hexahydro-[1,4]dioxino[2,3-f]isoquinoline-7-carboxamide,by the reaction and purification in the same manner as in Step 9 ofExample 252.

¹H NMR (300 MHz, CDCl₃): δ 0.27 (9H, s), 2.08-2.17 (2H, m), 2.43-2.64(3H, m), 2.84 (1H, dt, J=14.9, 5.9 Hz), 2.92-3.11 (2H, m), 3.73 (1H,ddd, J=12.3, 7.4, 4.9 Hz), 3.92-4.02 (1H, m), 4.20-4.30 (4H, m), 5.84(1H, s), 6.76 (1H, d, J=8.3 Hz), 6.79-6.87 (2H, m), 6.99 (1H, d, J=8.7Hz), 9.74 (1H, s).

Example 288(1-(((6R)-6-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,6,8,9-tetrahydrofuro[2,3-f]isoquinolin-7(2H)-yl)carbonyl)azetidin-3-yl)aceticacid (Step 1)

(R)—N-(3,5-Difluoro-4-(trimethylsilyl)phenyl)-2,3,6,7,8,9-hexahydrofuro[2,3-f]isoquinoline-6-carboxamidewas synthesized using7-(tert-butoxycarbonyl)-2,3,6,7,8,9-hexahydrofuro[2,3-f]isoquinoline-6-carboxylicacid and 3,5-difluoro-4-(trimethylsilyl)aniline, by the reaction andpurification in the same manner as in Steps 8 to 10 of Example 254.

¹H NMR (300 MHz, CDCl₃): δ 0.32 (9H, t, J=1.3 Hz), 1.90 (1H, brs), 2.70(2H, td, J=5.7, 3.0 Hz), 3.13 (2H, t), 3.20 (2H, t, J=8.7 Hz), 4.58 (2H,t, J=8.9 Hz), 4.65 (1H, s), 7.05-7.13 (4H, m), 9.42 (1H, s).

(Step 2)

The title compound was synthesized using(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2,3,6,7,8,9-hexahydrofuro[2,3-f]isoquinoline-6-carboxamideand benzyl 2-(azetidin-3-yl)acetate, by the reaction and purification inthe same manner as in Example 230 and Example 231.

¹H NMR (300 MHz, CDCl₃): δ 0.31 (9H, s), 2.72 (2H, dd, J=7.7, 1.7 Hz),2.75-2.86 (2H, m), 2.95-3.07 (1H, m), 3.22 (2H, t, J=8.7 Hz), 3.38-3.50(1H, m), 3.57-3.66 (1H, m), 3.70 (1H, dd, J=8.5, 5.9 Hz), 3.94 (1H, dd,J=8.5, 5.9 Hz), 4.16 (1H, t, J=8.3 Hz), 4.40 (1H, t, J=8.5 Hz), 4.59(2H, t, J=8.7 Hz), 5.63 (1H, s), 6.68 (1H, d, J=7.9 Hz), 7.03-7.12 (3H,m), 9.92 (1H, s).

Example 289(1-(((7R)-7-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2,3,9,10-tetrahydro[1,4]dioxino[2,3-f]isoquinolin-8(7H)-yl)carbonyl)azetidin-3-yl)aceticacid

The title compound was synthesized using benzyl 2-(azetidin-3-yl)acetateand(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2,3,7,8,9,10-hexahydro-[1,4]dioxino[2,3-f]isoquinoline-7-carboxamide,by the reaction and purification in the same manner as in Example 230and Example 231.

¹H NMR (300 MHz, CDCl₃): δ 0.31 (9H, s), 2.69-2.74 (2H, m), 2.75-2.91(2H, m), 2.95-3.07 (1H, m), 3.37-3.48 (1H, m), 3.56-3.66 (1H, m), 3.71(1H, dd, J=8.3, 5.7 Hz), 3.94 (1H, dd, J=8.5, 5.9 Hz), 4.16 (1H, t,J=8.5 Hz), 4.21-4.31 (4H, m), 4.39 (1H, t, J=8.5 Hz), 5.57 (1H, s), 6.68(1H, d), 6.79 (1H, d), 7.02-7.10 (2H, m), 9.93 (1H, s).

Example 290(1-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-propyl-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)azetidin-3-yl)aceticacid (Step 1)

A mixture of 1-(3-bromophenyl)propan-1-one (15.00 g, 70.40 mmol) andhydrazine monohydrate (8.54 mL, 176.00 mmol) in diethylene glycol (85mL) was stirred at room temperature for 20 min. To the mixture was addedpowderized potassium hydroxide (13.94 g, 211.20 mmol), and the mixturewas heated under reflux for 2 hr. The reaction mixture was cooled, icewater (500 mL) was added thereto, and 6N hydrochloric acid was addedthereto until the pH of the mixture became 3. Then, the mixture wasextracted three times with a mixed solvent of ethyl acetate/hexane(2:1). The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent; 2% ethyl acetate/hexane) to give 1-bromo-3-propylbenzene(11.61 g, 58.3 mmol, 83%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 0.93 (3H, t, J=7.4 Hz), 1.63 (2H, dq, J=15.0,7.3 Hz), 2.55 (2H, t), 7.07-7.17 (2H, m), 7.28-7.34 (2H, m).

(Step 2)

2-(tert-Butoxycarbonyl)-6-propyl-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid was synthesized using 1-bromo-3-propylbenzene, by the reaction andpurification in the same manner as in Steps 5 to 7 of Example 252 andSteps 3 to 7 of Example 254.

¹H NMR (300 MHz, CDCl₃): δ 0.93 (3H, t, J=7.4 Hz), 1.41-1.51 (9H, m),1.62 (2H, sxt, J=7.5 Hz), 2.54 (2H, t, J=7.7 Hz), 2.74-2.98 (2H, m),3.60-3.84 (2H, m), 5.36-5.56 (1H, m), 6.96 (1H, s), 7.03 (1H, d, J=7.9Hz), 7.37 (1H, d, J=7.9 Hz).

(Step 3)

(R)—N-(3,5-Difluoro-4-(trimethylsilyl)phenyl)-6-propyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamidewas synthesized using2-(tert-butoxycarbonyl)-6-propyl-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid and 3,5-difluoro-4-(trimethylsilyl)aniline, by the reaction andpurification in the same manner as in Steps 8 to 10 of Example 254.

¹H NMR (300 MHz, CDCl₃): δ 0.32 (9H, t, J=1.3 Hz), 0.94 (3H, t, J=7.4Hz), 1.62 (2H, sxt, J=7.5 Hz), 2.04 (1H, brs), 2.53 (2H, t), 2.69-2.79(1H, m), 2.83-2.94 (1H, m), 3.14 (2H, t), 4.66 (1H, s), 6.92 (1H, s),7.03 (1H, dd, J=7.9, 1.9 Hz), 7.06-7.13 (2H, m), 7.50 (1H, d, J=8.3 Hz),9.56 (1H, s).

(Step 4)

The title compound was synthesized using(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-propyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamide,by the reaction and purification in the same manner as in Example 230and Example 231.

¹H NMR (300 MHz, CDCl₃): δ 0.30 (9H, s), 0.94 (3H, t, J=7.4 Hz), 1.62(2H, sxt, J=7.5 Hz), 2.52-2.59 (2H, m), 2.69-2.74 (2H, m), 2.83-3.05(3H, m), 3.53-3.60 (2H, m), 3.72 (1H, dd, J=8.3, 5.7 Hz), 3.94 (1H, dd,J=8.5, 5.9 Hz), 4.18 (1H, t), 4.39 (1H, t, J=8.3 Hz), 5.62 (1H, s), 6.99(1H, s), 7.01-7.09 (3H, m), 7.14 (1H, d), 9.98 (1H, s).

Example 291 (1-(((7R)-7-((7-fluoro-1,l-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2,3,9,10-tetrahydro[1,4]dioxino[2,3-f]isoquinolin-8(7H)-yl)carbonyl)azetidin-3-yl)aceticacid

The title compound was synthesized using(R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2,3,7,8,9,10-hexahydro[1,4]dioxino[2,3-f]isoquinoline-7-carboxamideand benzyl 2-(azetidin-3-yl)acetate, by the reaction and purification inthe same manner as in Example 230 and Example 231.

¹H NMR (300 MHz, CDCl₃): δ 1.33 (6H, s), 1.89 (2H, t, J=7.4 Hz),2.66-2.89 (6H, m), 2.93-3.05 (1H, m), 3.35-3.46 (1H, m), 3.57-3.65 (1H,m), 3.69 (1H, dd, J=8.5, 5.9 Hz), 3.92 (1H, dd, J=8.5, 5.9 Hz), 4.15(1H, t), 4.21-4.30 (4H, m), 4.38 (1H, t, J=8.3 Hz), 5.57 (1H, s), 6.68(1H, d), 6.79 (1H, d), 7.10 (1H, s), 7.17 (1H, dd, J=1 2.1, 1.5 Hz),9.58 (1H, s).

Example 292 methyl4-((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)butanoate

Sodium triacetoxyborohydride (313 mg, 1.48 mmol) was added to a solutionof(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(96 mg, 0.25 mmol) and methyl 4-oxobutanoate (0.077 mL, 0.74 mmol) inethyl acetate (4 mL) at room temperature, and the mixture was stirredovernight at room temperature. To the reaction mixture was added water,and the mixture was extracted with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 0→75% ethylacetate/hexane) to give the title compound (93 mg, 0.189 mmol, 77%) as acolorless oil.

¹H NMR (300 MHz, CDCl₃): δ 0.27-0.39 (9H, m), 1.81-2.17 (2H, m),2.26-2.54 (3H, m), 2.56-2.81 (3H, m), 2.83-2.99 (1H, m), 3.15-3.27 (1H,m), 3.69 (3H, s), 3.77 (3H, s), 4.11 (1H, s), 6.63 (1H, d, J=2.6 Hz),6.68-6.82 (1H, m), 7.08-7.23 (2H, m), 7.35-7.47 (1H, m), 9.04-9.24 (1H,m).

Example 293 methyl4-(((1R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)butanoate

TEA (0.057 mL, 0.41 mmol) was added to a solution of(R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide(80 mg, 0.20 mmol) and methyl 4-(chlorosulfonyl)butanoate (61.7 mg, 0.31mmol) in DMF (2.0 mL) at room temperature, and the mixture was stirredovernight at room temperature. The reaction mixture was concentratedunder reduced pressure, and the obtained residue was purified by silicagel column chromatography (solvent; ethyl acetate/hexane) to give thetitle compound (30.0 mg, 0.054 mmol, 26.4%) as a colorless oil.

The compounds described in Examples 102 to 293 are as follows (Table1-12-Table 1-31).

TABLE 1-12 EXAMPLE IUPACNAME Structure ADDITIVE MS 102(1R)-N-(6-(1-(2,2-difluoro- ethoxy)-2-methylpropan-2-yl)-5-fluoropyridin-3 -yl)-2-((3-hydroxy- 1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4-tetrahydro- isoquinoline-1-carboxamide

563.2 (M + H) 103 (1R)-2-(cyanoacetyl)-N-(3,5-difluoro-4-(2-methyl-1-oxo-1- (pyrrolidin-1-yl)propan-2-yl)phenyl)-6-methoxy-1,2,3,4- tetrahydroisoquinoline-1- carboxamide

525.2 (M + H) 104 (1R)-N-(3,5-difluoro-4-(2- methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)- 6-methoxy-2-(3,3,3-trifluoropropanoyl)-1,2,3,4- tetrahydroisoquinoline-1- carboxamide

568.1 (M + H) 105 (1R)-N-(3,5-difluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1- yl)propan-2-yl)phenyl)-6-methoxy-2-(pyridin-3- ylacetyl)-1,2,3,4- tetrahydroisoquinoline-1-carboxamide

577.2 (M + H) 106 (1R)-N-(3,5-difluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1- yl)propan-2-yl)phenyl)-6-methoxy-2-((5-methyl-1,3,4- oxadiazol-2-yl)acetyl)-1,2,3,4-tetrahydroisoquinoline-1- carboxamide

582.2 (M + H) 107 (1R)-N-(3-fluoro-4-(trimethyl-silyl)phenyl)-2-((3-hydroxy- 1,2-oxazol-5-yl)carbonyl)-6-(methoxymethyl)-1,2,3,4- tetrahydroisoquinoline-1- carboxamide

496   (M − H) 108 ((2-((1R)-1-((3,5-difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)(methyl) amino)acetic acid

520.2 (M + H) 109 5-((1R)-1-((4-tert-butyl-3,5-difluorophenyl)carbamoyl)- 6-methoxy-3,4-dihydro-isoquinolin-2(1H)-yl)-5- oxopentanoic acid

487.3 (M − H) 110 5-((1R)-1-((3-fluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-(methoxy- methyl)-3,4-dihydro- isoquinolin-2(1H)-yl)-5-oxopentanoic acid

499.1 (M − H) 111 (5R)-N-(4-(ethyl(dimethyl) silyl)-3,5-difluorophenyl)-6-((3-hydroxy-1,2-oxazol-5- yl)carbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6- naphthyridine-6- carboxamide

517.1 (M + H)

TABLE 1-13 EXAMPLE IUPACNAME Structure ADDITIVE MS 112(5S)-N-(4-(ethyl(dimethyl)silyl)- 3,5-difluorophenyl)-6-((3-hydroxy-1,2-oxazol-5- yl)carbonyl)-2-methoxy- 5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide

517.1 (M + H) 113 (5R)-N-(4-(ethyl(dimethyl)silyl)-3,5-difluorophenyl)-6-((3- hydroxy-1,2-oxazol-5- yl)acetyl)-2-methoxy-5,6,7,8-tetrahydro-1,6- naphthyridine-5-carboxamide

531.1 (M + H) 114 5-((5R)-5-((4- (ethyl(dimethyl)silyl)-3,5-difluorophenyl)carbamoyl)- 2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5- oxopentanoic acid

520.2 (M + H) 115 (5R)-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)- 6-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-2-methoxy- 5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide

481.0 481.1 (M + H) 116 (5S)-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)- 6-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-2-methoxy- 5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide

481.2 (M + H) 117 (5R)-N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)- 6-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-2-methoxy- 5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide

495.1 (M + H) 118 5-((5R)-5-((7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)- 2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5- oxopentanoic acid

484.1 (M + H) 119 5-((1R)-1-((3,5-difluoro-4- (1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6- methoxy-3,4-dihydro- isoquinolin-2(1H)-yl)-5-oxopentanoic acid

517.1 (M − H) 120 (2S)-5-((1R)-1-((4-tert- butyl-3,5-difluorophenyl)carbamoyl)-6-methoxy-3,4- dihydroisoquinolin-2(1H)- yl)-2-hydroxy-5-oxopentanoic acid

503.0 (M − H) 121 (1R)-N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-2-((3-hydroxy-1,2-oxazol-5- yl)acetyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline- 1-carboxamide

528.0 (M − H)

TABLE 1-14 EXAMPLE IUPACNAME Structure ADDITIVE MS 122(5R)-N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-6-((3-hydroxy-1,2-oxazol-5- yl)carbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6- naphthyridine-5-carboxamide

503.1 (M + H) 123 (5S)-N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-6-((3-hydroxy-1,2-oxazol-5- yl)carbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6- naphthyridine-5-carboxamide

503.0 (M + H) 124 (5R)-N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-6-((3-hydroxy-1,2-oxazol-5- yl)acetyl)-2-methoxy- 5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide

517.1 (M + H) 125 5-((5R)-5-((3,5-difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-2-methoxy- 7,8-dihydro-1,6- naphthyridin-6(5H)-yl)-5-oxopentanoic acid

504   (M − H) 126 (5R)-N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-2-ethoxy-6-((3-hydroxy-1,2- oxazol-5-yl)carbonyl)- 5,6,7,8-tetrahydro-1,6-naphthyridine-5- carboxamide

517.1 (M + H) 127 (5S)-N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-2-ethoxy-6-((3-hydroxy-1,2- oxazol-5-yl)carbonyl)- 5,6,7,8-tetrahydro-1,6-naphthyridine-5- carboxamide

517.1 (M + H) 128 (5R)-N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-2-ethoxy-6-((3-hydroxy-1,2- oxazol-5-yl)acetyl)- 5,6,7,8-tetrahydro-1,6-naphthyridine-5- carboxamide

531.1 (M + H) 129 5-((5R)-5-(3,5-difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-2-ethoxy-7,8- dihydro-1,6-naphthyridin-6(5H-yl)-5-oxopentanoic acid

518.1 (M − H) 130 5-((1R)-1-(3,5-difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-(methoxy- methyl)-3,4-dihydro- isoquinolin-2(1H)-yl)-5-oxopentanoic acid

517.1 (M − H) 131 (1R)-N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-2-((3-hydroxy-1,2-oxazol-5- yl)carbonyl)-6-(methoxy-methyl)-1,2,3,4-tetrahydro- isoquinoline-1-carboxamide

516.1 (M + H)

TABLE 1-15 EXAMPLE IUPACNAME Structure ADDITIVE MS 132(1R)-N-(4-tert-butyl-3- fluorophenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6- (methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1- carboxamide

494.1 (M + H) 133 (1R)-N-(7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)-2-((3-hydroxy- 1,2-oxazol-5-yl)carbonyl)- 6-(methoxymethyl)-1,2,3,4-tetrahydro- isoquinoline-1-carboxamide

494.2 (M + H) 134 5-((1R)-1-((7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6- (methoxymethyl)-3,4- dihydroisoquinolin-2(1H)-yl)-5-oxopentanoic acid

495.1 (M − H) 135 5-((1R)-1-((3-fluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-methoxy- 3,4-dihydroisoquinolin- 2(1H)-yl)-5-oxopentanoicacid

485.1 (M − H) 136 (5R)-N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-6-((3-hydroxy-1,2-oxazol- 5-yl)carbonyl)-2-(methoxy-methyl)-5,6,7,8-tetrahydro- 1,6-naphthyridine-5- carboxamide

517.2 517.1 (M + H) 137 (1R)-N-(3,5-difluoro-4- (1-methoxy-2-methyl-propan-2-yl)phenyl)-2- ((3-hydroxy-1,2-oxazol- 5-yl)carbonyl)-6-(methoxymethyl)-1,2,3,4- tetrahydroisoquinoline-1- carboxamide

530.1 (M + H) 138 (5R)-N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-6-((3-hydroxy-1,2-oxazol- 5-yl)acetyl)-2-(methoxy-methyl)-5,6,7,8-tetrahydro- 1,6-naphthyridine-5- carboxamide

531.1 (M + H) 139 5-((5R)-5-((3,5-difluoro- 4-(trimethylsilyl)phenyl)carbamoyl)-2-(methoxy- methyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5- oxopentanoic acid

520.1 (M + H) 140 5-((5R)-5-((3-fluoro- 4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy- 7,8-dihydro-1,6- naphthyridin-6(5H)-yl)-5-oxopentanoic acid

488.2 (M + H) 141 5-((1R)-1-((3,5-difluoro- 4-(1-(2-methoxyethoxy)-2-methylpropan-2- yl)phenyl)carbamoyl)- 6-ethoxy-3,4-dihydro-isoquinolin-2(1H)-yl)-5- oxopentanoic acid

575.1 (M − H)

TABLE 1-16 EXAMPLE IUPACNAME Structure ADDITIVE MS 142(1R)-N-(3,5-difluoro-4- (1-(2-methoxyethoxy)- 2-methylpropan-2-yl)phenyl)-6-ethoxy-2- ((3-hydroxy-1,2-oxazol- 5-yl)carbonyl)-1,2,3,4-tetrahydroisoquinoline- 1-carboxamide

574.2 (M + H) 143 (1R)-N-(3,5-difluoro-4- (1-(2-methoxyethoxy)-2-methylpropan-2- yl)phenyl)-6-ethoxy-2- ((3-hydroxy-1,2-oxazol-5-yl)acetyl)-1,2,3,4- tetrahydroisoquinoline- 1-carboxamide

588.2 (M + H) 144 5-((1R)-1-((4-tert- butyl-3,5-difluoro-phenyl)carbamoyl)-6- (methoxymethyl)-3,4- dihydroisoquinolin-2(1H)-yl)-5- oxopentanoic acid

503.2 (M + H) 145 (5R)-2-ethoxy-N-(7- fluoro-1,1-dimethyl-2,3-dihydro-1H-inden- 5-yl)-6-((3-hydroxy- 1,2-oxazol-5-yl)carbonyl)-5,6,7,8- tetrahydro-1,6- naphthyridine-5- carboxamide

495.1 (M + H) 146 (5S)-2-ethoxy-N-(7- fluoro-1,1-dimethyl-2,3-dihydro-1H-inden- 5-yl)-6-((3-hydroxy- 1,2-oxazol-5-yl)carbonyl)-5,6,7,8- tetrahydro-1,6- naphthyridine-5- carboxamide

495.1 (M + H) 147 (5R)-2-ethoxy-N-(7- fluoro-1,1-dimethyl-2,3-dihydro-1H-inden- 5-yl)-6-((3-hydroxy- 1,2-oxazol-5-yl)acetyl)-5,6,7,8-tetrahydro- 1,6-naphthyridine- 5-carboxamide

509.2 (M + H) 148 5-((5R)-2-ethoxy-5-((7- fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5- yl)carbamoyl)-7,8-dihydro- 1,6-naphthyridin-6(5H)-yl)-5-oxopentanoic acid

498.2 (M + H) 149 (5R)-2-ethoxy-N-(3-fluoro- 4-(trimethylsilyl)phenyl)-6-((3-hydroxy-1,2-oxazol- 5-yl)carbonyl)-5,6,7,8- tetrahydro-1,6-naphthyridine-5- carboxamide

499.1 (M + H) 150 (5S)-2-ethoxy-N-(3-fluoro- 4-(trimethylsilyl)phenyl)-6-((3-hydroxy-1,2-oxazol- 5-yl)carbonyl)-5,6,7,8- tetrahydro-1,6-naphthyridine-5- carboxamide

499.1 (M + H) 151 (5R)-2-ethoxy-N-(3-fluoro- 4-(trimethylsilyl)phenyl)-6-((3-hydroxy-1,2-oxazol- 5-yl)acetyl)-5,6,7,8- tetrahydro-1,6-naphthyridine-5- carboxamide

513.1 (M + H)

TABLE 1-17 EXAM- PLE IUPACNAME Structure ADDITIVE MS 1525-((5R)-2-ethoxy-5-((3- fluoro-4-(trimethyl- silyl)phenyl)carbamoyl)-7,8-dihydro- 1,6-naphthyridin- 6(5H)-yl)-5- oxopentanoic acid

502.2 (M + H) 153 5-((1R)-1-((4-(1-(2,2- difluoroethoxy)-2-methylpropan-2-yl)-3,5- difluorophenyl)carbamoyl)- 6-ethoxy-3,4-dihydro-isoquinolin-2(1H)- yl)-5-oxopentanoic acid

581.1 (M − H) 154 (1R)-N-(4-(1-(2,2-difluoro- ethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)- 6-ethoxy-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)- 1,2,3,4-tetrahydro- isoquinoline-1-carboxamide

580.1 (M + H) 155 (1R)-N-(4-(1-(2,2-difluoro- ethoxy)-2-methylpropan-2-yl)-3,5-difluoro- phenyl)-6-ethoxy-2-((3- hydroxy-1,2-oxazol-5-yl)acetyl)-1,2,3,4- tetrahydroisoquinoline- 1-carboxamide

592.1 (M − H) 156 5-((1R)-1-((3,5-difluoro-4- (trimethylsilyl)phenyl)carbamoyl)- 6-methoxy-3,4-dihydro- isoquinolin-2(1H)-yl)-3-hydroxy-3-methyl-5- oxopentanoic acid

535.1 (M + H) 157 (1R)-N-(4-(1-(cyclopropyl- methoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)-2- ((3-hydroxy-1,2-oxazol-5-yl)acetyl)-6-methoxy- 1,2,3,4-tetrahydro- isoquinoline-1- carboxamide

568.1 (M − H) 158 (1R)-N-(4-(1-(cyclopropyl- methoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)-2- ((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy- 1,2,3,4-tetrahydro- isoquinoline- 1-carboxamide

556.2 (M + H) 159 (1R)-N-(4-(1-(2,2-difluoro- ethoxy)-2-methylpropan-2-yl)-3,5-difluorophenyl)-2- ((3-hydroxy-1,2- oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4- tetrahydroisoquinoline- 1-carboxamide

578.0 (M − H) 160 (1R)-N-(4-(1-(2,2-difluoro- ethoxy)-2-methylpropan-2-yl)-3,5-difluoro- phenyl)-2-((3- hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy- 1,2,3,4- tetrahydroisoquinoline- 1-carboxamide

564.0 (M − H) 161 5-((1R)-1-((4-(1-(cyclo- propylmethoxy)-2-methylpropan-2- yl)-3,5-difluoro- phenyl)carbamoyl)-6-methoxy-3,4-dihydro- isoquinolin-2(1H)-yl)- 5-oxopentanoic acid

557.2 (M − H)

TABLE 1-18 EXAM- ADDI- PLE IUPACNAME Structure TIVE MS 1625-((1R)-1-((4-(1-(2,2- trifluoroethoxy)-2- methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)- 6-methoxy-3,4- dihydroisoquinolin-2(1H)-yl)-5-oxopentanoic acid

567.1 (M − H) 163 (1R)-N-(3,5-difluoro-4-(1- methoxy-2-methylpropan-2-yl)phenyl)-6-ethoxy-2-((3- hydroxy-1,2-oxazol-5- yl)carbonyl)-1,2,3,4-tetrahydroisoquinoline-1- carboxamide

530.1 (M + H) 164 5-((1R)-1-((3,5-difluoro- 4-(1-methoxy-2-methylpropan-2-yl)phenyl) carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)- yl)-5-oxopentanoic acid

531.1 (M − H) 165 (1R)-N-(3,5-difluoro-4-(1- methoxy-2-methylpropan-2-yl)phenyl)-6-ethoxy-2-((3- hydroxy-1,2-oxazol-5-yl)acetyl)-1,2,3,4-tetrahydro- isoquinoline-1-carboxamide

542.1 (M − H) 166 5-((1R)-6-ethoxy-1-((4-(1- ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl) carbamoyl)-3,4- dihydroisoquinolin-2(1H)-yl)-5-oxopentanoic acid

547.2 (M + H) 167 (1R)-6-ethoxy-N-(4-(1-ethoxy- 2-methylpropan-2-yl)-3,5-difluorophenyl)-2-((3- hydroxy-1,2-oxazol-5- yl)carbonyl)-1,2,3,4-tetrahydroisoquinoline-1- carboxamide

544.2 (M + H) 168 (1R)-6-ethoxy-N-(4-(1- ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)- 2-((3-hydroxy-1,2-oxazol-5-yl)acetyl)-1,2,3,4- tetrahydroisoquinoline- 1-carboxamide

556.1 (M − H) 169 (1R)-N-(7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)-2-((3- hydroxy-1,2-oxazol-5- yl)acetyl)-6-(methoxy-methyl)-1,2,3,4-tetrahydro- isoquinoline-1-carboxamide

506.1 (M − H) 170 (1R)-N-(4-(1-ethoxy-2- methylpropan-2-yl)-3,5-difluorophenyl)-2-((3-hydroxy- 1,2-oxazol-5-yl)acetyl)-6-methoxy-1,2,3,4- tetrahydroisoquinoline-1- carboxamide

542.2 (M − H) 171 (1R)-N-(4-(1-ethoxy-2- methylpropan-2-yl)-3,5-difluorophenyl)-2-((3- hydroxy-1,2-oxazol-5- yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydro- isoquinoline-1-carboxamide

530.1 (M + H)

TABLE 1-19 EXAMPLE IUPACNAME Structure ADDITIVE MS 172 5-((1R)-1-((4-(1-ethoxy-2-methylpropan- 2-yl)-3,5-difluoro- phenyl)carbamoyl)-6-methoxy-3,4- dihydroisoquinolin-2(1H)- yl)-5-oxopentanoic acid

531.1 (M − H) 173 (5R)-N-(4-(ethyl(dimethyl) silyl)-3,5-difluorophenyl)-6-((3-hydroxy-1,2- oxazol-5-yl)acetyl)-2- (methoxymethyl)-5,6,7,8-tetrahydro-1,6- naphthyridine-5- carboxamide

545.1 (M + H) 174 (5R)-N-(4-(ethyl(dimethyl) silyl)-3,5-difluorophenyl)-6-((3-hydroxy-1,2- oxazol-5-yl)carbonyl)-2- (methoxymethyl)-5,6,7,8-tetrahydro-1,6- naphthyridine-5- carboxamide

531.1 (M + H) 175 5-((5R)-5-((4-(ethyl (dimethyl)silyl)-3,5-difluorophenyl)carbamoyl)- 2-(methoxymethyl)-7,8-dihydro-1,6-naphthyridin- 6(5H)-yl)-5-oxopentanoic acid

534.2 (M + H) 176 5-((1R)-1-((7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6- methoxy-3,4-dihydro- isoquinolin-2(1H)-yl)-5-oxopentanoic acid

483.1 (M + H) 177 4-((5R)-5-((7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2- methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)- 4-oxobutanoic acid

470.2 (M + H) 178 4-((5R)-5-((3,5-difluoro- 4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8- dihydro-1,6-naphthyridin-6(5H)-yl)-4-oxobutanoic acid

490.2 (M − H) 179 5-((1R)-1-((3,5-difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6- ethoxy-3,4-dihydro- isoquinolin-2(1H)-yl)-5- oxopentanoicacid

517.1 (M − H) 180 4-((1R)-1-((3,5-difluoro- 4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4- dihydroisoquinolin-2(1H)- yl)-4-oxobutanoicacid

503.0 (M − H) 181 5-((1R)-6-((difluoromethoxy) methyl)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl) carbamoyl)-3,4- dihydroisoquinolin-2(1H)-yl)-5-oxopentanoic acid

553.0 (M − H)

TABLE 1-20 EXAMPLE IUPACNAME Structure ADDITIVE MS 1825-((1R)-6-ethoxy-1- ((7-fluoro-1,1-dimethyl- 2,3-dihydro-1H-inden-5-yl)carbamoyl)-3,4- dihydroisoquinolin-2(1H)- yl)-5-oxopentanoic acid

497.2 (M + H) 183 5-((1R)-6-ethoxy-1-((3- fluoro-4-(trimethyl-silyl)phenyl)carbamoyl)- 3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoic acid

499.0 (M − H) 184 5-((1R)-1-((2,5-difluoro- 4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4- dihydroisoquinolin-2(1H)- yl)-5-oxopentanoicacid

517.1 (M − H) 185 5-((1-((3,5-difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-methoxy- 3,4-dihydroisoquinolin- 2(1H)-yl)carbonyl)-1-methyl-1H-pyrazole- 3-carboxylic acid

543.1 (M + H) 186 ethyl N-((1-((3,5- difluoro-4-(trimethyl-silyl)phenyl)carbamoyl)- 6-methoxy-3,4- dihydroisoquinolin-2(1H)-yl)carbonyl)-beta-alaninate

534.1 (M + H) 187 (1R)-N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-2-((2,4-dioxo-1,3-thiazolidin- 5-yl)acetyl)-6-methoxy- 1,2,3,4-tetrahydro-isoquinoline-1-carboxamide

546.0 (M − H) 188 N-(((1R)-1-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-methoxy- 3,4-dihydroisoquinolin- 2(1H)-yl)carbonyl)-beta-alanine

506.1 (M + H) 189 5-(2-((1R)-1-((4- tert-butyl-3,5-difluorophenyl)carbamoyl)- 6-methoxy-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1,2-oxazole- 3-carboxylic acid

528.0 (M + H) 190 5-((1R)-1-((3,5- difluoro-4-(trimethyl-silyl)phenyl)carbamoyl- 6-(oxetan-3-yloxy)- 3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoic acid

545.0 (M − H) 191 5-((1R)-6-(3,3-difluoro- azetidin-1-yl)-1-((7-fluoro-1,1- dimethyl-2,3-dihydro-1H- inden-5-yl)carbamoyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-5-oxopentanoic acid

544.1 (M + H)

TABLE 1-21 EXAMPLE IUPACNAME Structure ADDITIVE MS 192(1R)-2-(5-amino-5- oxopentanoyl)-N- (3,5-difluoro-4-(trimethylsilyl)phenyl)- 6-methoxy-1,2,3,4- tetrahydroisoquinoline-1-carboxamide

504.1 (M + H) 193 4-((1R)-6-(difluoro- methoxy)-1-((3-fluoro-4-(trimethylsilyl)phenyl) carbamoyl)-3,4-dihydro- isoquinolin-2(1H)-yl)-4-oxobutanoic acid

507.1 (M − H) 194 5-((1R)-6-(difluoro- methoxy)-1-((3-fluoro-4-(trimethylsilyl)phenyl) carbamoyl)-3,4-dihydro- isoquinolin-2(1H)-yl)-5-oxopentanoic acid

521.0 (M − H) 195 4-((1R)-6-(difluoro- methoxy)-1-((3,5-difluoro-4-(trimethyl- silyl)phenyl)carbamoyl)- 3,4-dihydroiso-quinolin-2(1H)-yl)- 4-oxobutanoic acid

525.0 (M − H) 196 5-((1R)-6-(difluoro- methoxy)-1-((3,5-difluoro-4-(trimethyl- silyl)phenyl)carbamoyl)- 3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoic acid

538.9 (M − H) 197 4-((1R)-6-(2,2- difluoroethoxy)-1-((3-fluoro-4-(trimethyl- silyl)phenyl)carbamoyl)- 3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutanoic acid

521.0 (M − H) 198 5-((1R)-6-(2,2- difluoroethoxy)-1- ((3-fluoro-4-(trimethylsilyl)phenyl) carbamoyl)-3,4-dihydro- isoquinolin-2(1H)-yl)-5-oxopentanoic acid

537.1 (M + H) 199 4-((1R)-6-(2,2- difluoroethoxy)-1- ((3,5-difluoro-4-(trimethylsilyl)phenyl) carbamoyl)-3,4-dihydro- isoquinolin-2(1H)-yl)-4-oxobutanoic acid

538.9 (M − H) 200 5-((1R)-6-(2,2- difluoroethoxy)-1- ((3,5-difluoro-4-((trimethylsilyl)phenyl) carbamoyl)-3,4-dihydro- isoquinolin-2(1H)-yl)-5-oxopentanoic acid

555.0 (M + H) 201 4-(1R)-1-((3- fluoro-4-(trimethyl-silyl)phenyl)carbamoyl)- 6-(2,2,2-trifluoroethoxy)-3,4-dihydroisoquinolin- 2(1H)-yl)-4- oxobutanoic acid

539.0 (M − H)

TABLE 1-22 EXAMPLE IUPACNAME Structure ADDITIVE MS 2025-((1R)-1-((3-fluoro- 4-(trimethylsilyl)phenyl) carbamoyl)-6-(2,2,2-trifluoroethoxy)-3,4- dihydroisoquinolin-2(1H)- yl)-5-oxopentanoic acid

555.0 (M + H) 203 4-((1R)-1-((3,5-difluoro- 4-(trimethylsilyl)phenyl)carbamoyl)-6-(2,2,2- trifluoroethoxy)-3,4-dihydro-isoquinolin-2(1H)-yl)-4- oxobutanoic acid

559.0 (M + H) 204 5-((1R)-1-((3,5-difluoro- 4-(trimethylsilyl)phenyl)carbamoyl)-6-(2,2,2- trifluoroethoxy)-3,4-dihydro-isoquinolin-2(1H)-yl)-5- oxopentanoic acid

573.1 (M + H) 205 4-((1R)-6-(difluoro- methoxy)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro- 1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-4-oxobutanoic acid

503.0 (M − H) 206 5-((1R)-6-(difluoro- methoxy)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro- 1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-5-oxopentanoic acid

519.1 (M + H) 207 4-((1R)-6-(2,2-difluoro- ethoxy)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H- inden-5-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)- yl)-4-oxobutanoic acid

517.0 (M − H) 208 5-((1R)-6-(2,2-difluoro- ethoxy)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H- inden-5-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)- yl)-5-oxopentanoic acid

533.1 (M + H) 209 (4R)-5-((1R)-1- ((3,5-difluoro-4-(trimethylsilyl)phenyl) carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)- yl)-4-hydroxy-5-oxopentanoic acid

535.0 (M + H) 210 6-((1R)-6-ethoxy-1-((7- fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5- yl)carbamoyl)-3,4- dihydroisoquinolin-2(1H)-yl)-6-oxohexanoic acid

511.0 (M + H) 211 6-((1R)-6-ethoxy- 1-((3-fluoro-4-(trimethylsilyl)phenyl) carbamoyl)-3,4-dihydro- isoquinolin-2(1H)-yl)-6-oxohexanoic acid

513.0 (M − H)

TABLE 1-23 EXAMPLE IUPACNAME Structure ADDITIVE MS 2125-((5R)-2-(difluoro- methoxy)-5-((7-fluoro- 1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)- 7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-oxopentanoic acid

518.0 (M − H) 213 (1R)-N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-2-((1,1-dioxido-4-oxo-1,2,5- thiadiazolidin-2-yl)acetyl)-6-ethoxy-1,2,3,4-tetrahydro- isoquinoline-1-carboxamide

578.9 (M − H) 214 (5R)-6-((1,1-dioxido-4- oxo-1,2,5-thiadiazolidin-2-yl)acetyl)-N-(7-fluoro- 1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy- 5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide

546.0 (M + H) 215 5-((1R)-1-((7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6- (2,2,2-trifluoroethoxy)-3,4-dihydroisoquinolin-2(1H)- yl)-5-oxopentanoic acid

549.0 216 (4R)-4-amino-5-((1R)-1- ((3,5-difluoro-4-(trimethyl-silyl)phenyl)carbamoyl)-6- ethoxy-3,4-dihydro- isoquinolin-2(1H)-yl)-5-oxopentanoic acid

534.0 (M + H) 217 5-((1R)-1-((7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6- isopropoxy-3,4- dihydroisoquinolin-2(1H)-yl)-5-oxopentanoic acid

509.1 (M − H) 218 5-((1R)-6-(cyclopropyl- methoxy)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro- 1H-inden-5-yl)carbamoyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-5-oxopentanoic acid

523.1 (M + H) 219 5-((1R)-1-((7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6- propoxy-3,4-dihydro- isoquinolin-2(1H)-yl)-5-oxopentanoic acid

508.8 (M − H) 220 (3-(((5R)-5-((7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2- methoxy-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)carbonyl)azetidin-1- yl)acetic acid

511.0 (M + H) 221 5-((1R)-1-((3-cyano- 4-(trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4- dihydroisoquinolin-2(1H)- yl)-5-oxopentanoicacid

506.1 (M − H)

TABLE 1-24 EXAM- ADDI- PLE IUPACNAME Structure TIVE MS 222(2E)-4-((1R)-1- ((3,5-difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4- dihydroisoquinolin-2(1H)- yl)-4-oxobut-2-enoicacid

486.9 (M − H) 223 (1R)-N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-2-(((3S)-1,1-dioxido-4-oxo- 1,2,5-thiadiazolidin-3-yl)acetyl)-6-ethoxy-1,2,3,4- tetrahydroisoquinoline- 1-carboxamide

578.9 (M − H) 224 (1R)-2-(((3S)-1,1-dioxido- 4-oxo-1,2,5-thiadiazolidin-3-yl)acetyl)-6-ethoxy-N- (7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)- 1,2,3,4-tetrahydroisoquinoline- 1-carboxamide

559.0 (M + H) 225 3-((((5R)-5-((7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2- methoxy-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)carbonyl)oxy)propanoic acid

486.0 (M + H) 226 4-((((5R)-5-((7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2- methoxy-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)carbonyl)oxy)butanoic acid

498.0 (M − H) 227 N-(((1R)-1-((3,5- difluoro-4-(trimethyl-silyl)phenyl)carbamoyl)-6- ethoxy-3,4-dihydro-isoquinolin-2(1H)-yl)carbonyl)- beta-alanine

520.1 (M + H) 228 1-(((1R)-1-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4- dihydroisoquinolin-2(1H)-yl)carbonyl)pyrrolidine-3- carboxylic acid

546.0 (M + H) 229 5-((1R )-1-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4- dihydroisoquinolin-2(1H)-yl)-4,5-dioxopentanoic acid

531.1 (M − H) 230 benzyl (1-(((1R)-1- ((3,5-difluoro-4-(trimethylsilyl)phenyl) carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)- yl)carbonyl)azetidin-3- yl)acetate

636.3 (M + H) 231 (1-(((1R)-1-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4- dihydroisoquinolin-2(1H)-yl)carbonyl)azetidin-3- yl)acetic acid

546.1 (M + H)

TABLE 1-25 EXAM- ADDI- PLE IUPACNAME Structure TIVE MS 232 benzyl(1-(((1R)-6- ethoxy-1-((7-fluoro- 1,1-dimethyl-2,3- dihydro-1H-inden-5-yl)carbamoyl)-3,4- dihydroisoquinolin-2(1H)- yl)carbonyl)azetidin-3-yl)acetate

614.3 (M + H) 233 (1-(((1R)-6-ethoxy-1- ((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden- 5-yl)carbamoyl)-3,4- dihydroisoquinolin-2(1H)-yl)carbonyl)azetidin-3- yl)acetic acid

524.3 (M + H) 234 (2Z)-4-((1R)-1- ((3,5-difluoro-4-(trimethylsilyl)phenyl) carbamoyl)-6-methoxy- 3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobut-2- enoic acid

487.1 (M − H) 235 5-((1R)-1-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-(methyl- sulfonyl)-3,4- dihydroisoquinolin-2(1H)-yl)-5-oxopentanoic acid

551.1 (M − H) 236 5-((1R)-6-ethoxy-1- ((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5- yl)carbamoyl)-3,4- dihydroisoquinolin-2(1H)-yl)-3-hydroxy-3-methyl-5- oxopentanoic acid

527.2 (M + H) 237 tert-butyl (((1R)-1- ((3,5-difluoro-4-(trimethylsilyl)phenyl) carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)- yl)sulfonyl)carbamate

582.3 (M − H) 238 4-((((1R)-1-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4- dihydroisoquinolin-2(1H)-yl)carbonyl)amino)butanoic acid

534.2 (M + H) 239 4-(((1R)-1-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4- dihydroisoquinolin-2(1H)-yl)carbonyl)morpholine-2- carboxylic acid

562.2 (M + H) 240 5-((1R)-1-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4- dihydroisoquinolin-2(1H)-yl)-3-hydroxy-3-methyl-5- oxopentanoic acid

549.2 (M + H) 241 5-((1R)-6-ethoxy-1-((7- fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5- yl)carbamoyl)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2-dimethyl-5- oxopentanoic acid

525.3 (M + H)

TABLE 1-26 EXAMPLE IUPACNAME Structure ADDITIVE MS 2424-((((1R)-1-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-methoxy- 3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)amino)butanoic acid

520.2 (M + H) 243 4-((((1R)-1-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4- dihydroisoquinolin-2(1H)-yl)sulfonyl)amino)butanoic acid

570.2 (M + H) 244 N-(((1R)-1-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4- dihydroisoquinolin-2(1H)-yl)carbonyl)-2-methylalanine

520.2 (M + H) 245 benzyl N-(((1R)-1- ((3,5-difluoro-4-(trimethylsilyl)phenyl) carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)- yl)carbonyl)-D-alaninate

596.2 (M + H) 246 N-(((1R)-1-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4- dihydroisoquinolin-2(1H)-yl)carbonyl)-D-alanine

506.3 (M + H) 247 5-((1R)-6-cyano-1- ((3,5-difluoro-4-(trimethylsilyl)phenyl) carbamoyl)-3,4-dihydro- isoquinolin-2(1H)-yl)-5-oxopentanoic acid

498.2 (M − H) 248 (4S)-5-((1R)-1- ((3,5-difluoro-4-(trimethylsilyl)phenyl) carbamoyl)-6-methoxy- 3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxy- 5-oxopentanoic acid

521.2 (M + H) 249 N-(((1R)-1-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-methoxy- 3,4-dihydroisoquinolin- 2(1H)-yl)carbonyl)-L-alanine

506.3 (M + H) 250 5-((5R)-5-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-2-isopropyl- 7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-oxopentanoic acid

518.2 (M + H) 251 5-((5R)-5-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-2-propyl- 7,8-dihydro- 1,6-naphthyridin-6(5H)-yl)-5-oxopentanoic acid

518.2 (M + H)

TABLE 1-27 EXAMPLE IUPACNAME Structure ADDITIVE MS 252 5-((5R)-5-((3,5-difluoro-4- (trimethylsilyl)phenyl) carbamoyl)-2,3,7,8-tetrahydrofuro[2,3- g]isoquinolin-6(5H)-yl)- 5-oxopentanoic acid

515.1 (M − H) 253 5-((1R)-1-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-methoxy- 5-methyl-3,4-dihydro- isoquinolin-2(1H)-yl)-5-oxopentanoic acid

519.1 (M + H) 254 5-((6R)-6-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-8,9- dihydro[1,3]dioxolo[4,5- f]isoquinolin-7(6H)-yl)-5-oxopentanoic acid

519.2 (M + H) 255 5-((5R)-5-((7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)- 2,3,7,8-tetrahydro- furo[2,3-g]isoquinolin-6(5H)-yl)- 5-oxopentanoic acid

493.2 (M − H) 256 5-((6R)-6-((7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-8,9- dihydro[1,3]dioxolo[4,5-f]isoquinolin-7(6H)-yl)- 5-oxopentanoic acid

497.2 (M + H) 257 N-(((1R)-1-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-methoxy- 3,4-dihydroisoquinolin- 2(1H)--yl)carbonyl)-N-methyl-beta-alanine

520.2 (M + H) 258 1-(((1R)-1-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-methoxy- 3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)azetidine- 3-carboxylic acid

518.2 (M + H) 259 1-(((1R)-1-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4- dihydroisoquinolin-2(1H)-yl)carbonyl)azetidine-3- carboxylic acid

532.2 (M + H) 260 (1-(((1R)-1-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-methoxy- 3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)azetidin- 3-yl)acetic acid

532.1 532.2 (M + H) 261 5-((1R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H- inden-5-yl)carbamoyl)-6- methoxy-5-methyl-3,4-dihydroisoquinolin- 2(1H)-yl)-5-oxopentanoic acid

497.2 (M + H)

TABLE 1-28 EXAM- ADDI- PLE IUPACNAME Structure TIVE MS 2625-((1R)-1-((7-fluoro- 1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)- 6-propyl-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoic acid

495.3 (M + H) 263 benzyl N-(((1R)-1- ((3,5-difluoro-4-(trimethylsilyl)phenyl) carbamoyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)- yl)carbonyl)glycinate

582.2 (M + H) 264 N-(((1R)-1-((3,5- difluoro-4-(trimethyl-silyl)phenyl)carbamoyl)- 6-methoxy-3,4- dihydroisoquinolin-2(1H)-yl)carbonyl)glycine

492.2 (M + H) 265 (4S)-5-((1R)-6-ethoxy-1- ((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden- 5-yl)carbamoyl)-3,4- dihydroisoquinolin-2(1H)-yl)-4-methyl-5-oxopentanoic acid

509.3 (M − H) 266 (2S)-5-((1R)-6-ethoxy-1- ((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden- 5-yl)carbamoyl)-3,4- dihydroisoquinolin-2(1H)-yl)-2-methyl-5-oxopentanoic acid

511.2 (M + H) 267 ((1-(((1R)-1-((3,5- difluoro-4-(trimethylsilyl)phenyl) carbamoyl)-6-methoxy- 3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)azetidin- 3-yl)oxy)acetic acid

548.2 (M + H) 268 (4R)-5-((1R)-6-ethoxy-1- ((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden- 5-yl)carbamoyl)-3,4- dihydroisoquinolin-2(1H)-yl)-4-methyl-5-oxopentanoic acid

509.3 (M − H) 269 (2R)-5-((1R)-6-ethoxy-1- ((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden- 5-yl)carbamoyl)-3,4- dihydroisoquinolin-2(1H)-yl)-2-methyl-5-oxopentanoic acid

511.1 (M + H) 270 5-((5R)-2-(difluoromethoxy)- 5-((3,5-difluoro-4-(trimethylsilyl)phenyl) carbamoyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)- 5-oxopentanoic acid

540.1 (M − H) 271 (1-(((6R)-6-((7-fluoro- 1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)- 8,9-dihydro[1,3]dioxolo[4,5-f]isoquinolin-7(6H)- yl)carbonyl)azetidin-3- yl)acetic acid

524.2 (M + H)

TABLE 1-29 EXAMPLE IUPACNAME Structure ADDITIVE MS 272(1-(((6R)-6-((3,5- difluoro-4- (trimethylsilyl)phenyl) carbamoyl)-8,9-dihydro[1,3]dioxolo[4,5 -f]isoquinolin-7(6H)- yl)carbonyl)azetidin-3-yl)acetic acid

546.1 (M + H) 273 (1-(((5R)-5-((7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2- methoxy-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)carbonyl)azetidin-3- yl)acetic acid

511.2 (M + H) 274 (1-(((1R)-l -((3,5- difluoro-4-(trimethyl-silyl)phenyl)carbamoyl)- 6-methoxy-3,4- dihydroisoquinolin-2(1H)-yl)carbonyl)-3- hydroxyazetidin-3-yl)acetic acid

548.2 (M + H) 275 (1-(((1R)-1-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-(methoxy- methyl)-3,4-dihydroiso- quinolin-2(1H)-yl)carbonyl)azetidin-3- yl)acetic acid

546.2 (M + H) 276 3-((((1R)-1- ((3,5-difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-methoxy- 3,4-dihydroisoquinolin- 2(1H)-yl)carbonyl)oxy)propanoic acid

507.2 (M + H) 277 3-((((1R)-1-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-6-ethoxy-3,4- dihydroisoquinolin-2(1H)-yl)carbonyl)oxy)propanoic acid

521.2 (M + H) 278 (1-(((5R)-2-(difluoro- methoxy)-5-((3,5- difluoro-4-(trimethylsilyl)phenyl) carbamoyl)-7,8-dihydro- 1,6-naphthyridin-6(5H)-yl)carbonyl)azetidin-3- yl)acetic acid

567.1 (M − H) 279 (1-(((1R)-1-((3- fluoro-4-(trimethyl-silyl)phenyl)carbamoyl)- 6-methoxy-3,4- dihydroisoquinolin-2(1H)-yl)carbonyl)azetidin-3- yl)acetic acid

514.1 (M + H) 280 (1-(((1R)-6-ethoxy-1- ((3-fluoro-4-(trimethylsilyl)phenyl) carbamoyl)-3,4-dihydro- isoquinolin-2(1H)-yl)carbonyl)azetidin-3- yl)acetic acid

528.2 (M + H) 281 (1-(((5R)-5-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-2-methoxy- 7,8-dihydro-1,6- naphthyridin-6(5H)-yl)carbonyl)azetidin-3- yl)acetic acid

533.2 (M + H)

TABLE 1-30 EXAMPLE IUPACNAME Structure ADDITIVE MS 2825-((5R)-5-((7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2- methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)- 5-oxopentanoic acid monosulfate dihydrate

H₂SO₄ 2H₂O 484.3 (M + H) 283 (1-(((1R)-6-(difluoro-methoxy)-1-((3,5-difluoro- 4-(trimethylsilyl)phenyl)carbamoyl)-3,4-dihydroiso- quinolin-2(1H)-yl)carbonyl)azetidin-3-yl)acetic acid

568.2 (M + H) 284 5-((6R)-6-((7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)- 3,6,8,9-tetrahydrofuro[2,3-f]isoquinolin-7(2H)-yl)- 5-oxopentanoic acid

495.1 (M + H) 285 5-((7R)-7-((7-fluoro-1,1- dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)- 2,3,9,10- tetrahydro[1,4]dioxino[2,3-f]isoquinolin-8(7H)-yl)-5- oxopentanoic acid

509.2 (M − H) 286 5-((6R)-6-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-3,6,8,9- tetrahydrofuro[2,3- f]isoquinolin-7(2H)-yl)-5-oxopentanoic acid

517.3 (M + H) 287 5-((7R)-7-((3,5- difluoro-4- (trimethylsilyl)phenyl)carbamoyl)-2,3,9,10- tetrahydro[1,4]dioxino[2,3-f]isoquinolin-8(7H)-yl)-5- oxopentanoic acid

533.2 (M + H) 288 (1-(((6R)-6-((3,5- difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-3,6,8,9- tetrahydrofuro[2,3- f]isoquinolin-7(2H)-yl)carbonyl)azetidin-3- yl)acetic acid

544.2 (M + H) 289 (1-(((7R)-7-((3,5- difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2,3,9,10- tetrahydro[1,4]dioxino[2,3-f]isoquinolin-8(7H)- yl)carbonyl)azetidin-3- yl)acetic acid

560.1 (M + H) 290 (1-(((1R)-1-((3,5- difluoro-4-(trimethyl-silyl)phenyl)carbamoyl)- 6-propyl-3,4- dihydroisoquinolin-2(1H)-yl)carbonyl)azetidin-3- yl)acetic acid

544.2 (M + H) 291 (1-(((7R)-7-((7-fluoro- 1,1-dimethyl-2,3-dihydro-1H-inden- 5-yl)carbamoyl)-2,3,9,10- tetrahydro[1,4]dioxino[2,3-f]isoquinolin-8(7H)- yl)carbonyl)azetidin-3- yl)acetic acid

538.3 (M + H)

TABLE 1-31 EXAMPLE IUPACNAME Structure ADDITIVE MS 292 methyl 4-((1R)-1-((3,5-difluoro-4- (trimethylsilyl)phenyl) carbamoyl)-6-methoxy-3,4-dihydroisoquinolin- 2(1H)-yl)butanoate

491.2 (M + H) 293 methyl 4-(((1R)-1- ((3,5-difluoro-4-(trimethylsilyl)phenyl) carbamoyl)-6-methoxy- 3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)butanoate

555.2 (M + H)

Experimental Example 1 RORγt Binding Test Using Fluorescent-LabeledCholesterol

The binding activity of the test compound to RORγt was measured by atime resolved fluorescence resonance energy transfer method (TR-FRET)utilizing histidine-tagged RORγt, fluorescent-labeled cholesterol(BODIPY-cholesterol, AVIVA), and terbium-labeled anti-histidine tagantibody (Invitrogen). First, a test compound diluted with an assaybuffer (20 mM Tris-HCl (pH 7.5), 100 mM NaCl, 1 mM DTT, 0.1% BSA) wasadded to a 384 well plate by 3 μL. Then, RORγt diluted with an assaybuffer to 240 nM was added by 3 μL, after which fluorescent-labeledcholesterol diluted with the assay buffer to 12 μM was added by 3 μL,and the mixture was stood at room temperature for 20 min. Thereafter, aterbium-labeled anti-histidine tag antibody diluted with the assaybuffer to 8 nM was added by 3 μL. The mixture was stood at roomtemperature for 20 min, and fluorescence intensity (excitationwavelength 320 nm, fluorescence wavelength 520 nm, delay time 100microseconds) was measured by Envision (PerkinElmer).

The results (binding inhibitory rate of fluorescent-labeled cholesterolto RORγt at test compound 1 UM) measured by the above-mentioned methodare shown in Tables 2-1 to 2-6.

Experimental Examples 1-2 RORγt Binding Test Using Fluorescent-LabeledSynthetic Ligand

The fluorescent-labeled synthetic cholesterol ligand was synthesized asfollows.

(Step 1)

A solution of (4-(methoxymethyl)phenyl)boronic acid (999 mg, 6.02 mmol),glyoxylic acid monohydrate (554 mg, 6.02 mmol) and diallylamine (0.741mL, 6.02 mmol) in acetonitrile (12 mL) stirred was at 60° C. for 5 hr.The reaction mixture was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography (Diol,solvent; ethyl acetate), and crystallized from ethyl acetate to give2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetic acid (200 mg, 0.726mmol, 12.07%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ 3.04-3.46 (7H, m), 4.39 (2H, s), 4.43 (1H,s), 5.04-5.23 (4H, m), 5.78 (2H, ddt, J=16.9, 10.5, 6.3 Hz), 7.23-7.40(4H, m).

(Step 2)

To a solution of 3,5-difluoro-4-(trimethylsilyl)aniline (6.69 g, 33.25mmol), 2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetic acid (11.9 g,43.22 mmol), DMAP (4.47 g, 36.57 mmol) and DIEA (29.0 mL, 166.23 mmol)in ethyl acetate (200 mL) was added T3P (29.3 mL, 49.87 mmol), and themixture was stirred at 80° C. for 1 hr. To the reaction mixture wereadded water and ethyl acetate, and the organic layer was separated. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 3→35% ethyl acetate/hexane) to give2-(diallylamino)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(9.00 g, 19.62 mmol, 59.0%) as a pale yellow oil.

(Step 3)

A solution of2-(diallylamino)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(1.64 g, 3.58 mmol), 1,3-dimethylbarbituric acid (1.173 g, 7.51 mmol)and Pd(PPh₃)₄ (0.165 g, 0.14 mmol) in THF (15 mL) was stirred overnightunder argon gas atmosphere at room temperature. The obtained residue waspurified by silica gel column chromatography (NH, solvent gradient;5→75% ethyl acetate/hexane) to give2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(470.5 mg, 1.243 mmol, 34.8%) as a pale yellow oil.

(Step 4)

To a solution of2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(470 mg, 1.24 mmol) and DIEA (0.651 mL, 3.73 mmol) in THF (10 mL) wasadded allyl chloroformate (0.158 mL, 1.49 mmol) at 0° C., and themixture was stirred for 1 hr. To the reaction mixture were added waterand ethyl acetate, and the organic layer was separated. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 0→10%ethyl acetate/hexane) to give allyl(2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(297 mg, 0.641 mmol, 51.7%) as a white solid.

(Step 5)

Allyl(2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(296 mg) was resolved by chiral column chromatography. The fractionhaving a shorter retention time was concentrated to give allyl(R)-(2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(108.5 mg, >99.9% ee) as a white solid.

purification condition by chiral column chromatography

column: CHIRALPAK AD (NF001) 50 mmID×500 mmL

solvent: hexane/EtOH=600/400

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 6)

A solution of allyl(R)-(2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(109 mg, 0.24 mmol), 1,3-dimethylbarbituric acid (81 mg, 0.52 mmol) andPd(PPh₃)₄(10.89 mg, 9.43 μmol) in THF (1571 μL) was stirred under argongas atmosphere at room temperature for 6 hr. The reaction solution wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (NH, solvent gradient;40→80% ethyl acetate/hexane) to give(R)-2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.263 mmol, 112%) as a yellow oil.

(Step 7)

To a solution of(R)-2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(9.07 mg, 0.02 mmol) in DMF (0.5 ml) was added1-((5-((2Z)-2-((1-(difluoroboryl)-3,5-dimethyl-1H-pyrrol-2-yl)methylene)-2H-pyrrol-5-yl)pentanoyl)oxy)pyrrolidine-2,5-dione(BODIPY (registered trademark) FL-C5 succinimidyl ester) (5.0 mg, 0.01mmol) at room temperature, and the mixture was stirred at roomtemperature for 3 hr. To the reaction mixture was added water, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent; ethyl acetate/hexane), andthen preparative HPLC (C18, mobile phase: water/acetonitrile (containing0.1% TFA)) to give5-((2Z)-2-((1-(difluoroboryl)-3,5-dimethyl-1H-pyrrol-2-yl)methylene)-2H-pyrrol-5-yl)-N-((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)pentanamide(3.8 mg, 5.58 μmol, 46.6%) as an orange solid, which is afluorescent-labeled synthetic ligand.

¹H NMR (300 MHz, CDCl₃): δ 0.31 (9H, t, J=1.3 Hz), 1.71-1.87 (4H, m),2.25 (3H, s), 2.32-2.42 (2H, m), 2.53 (3H, s), 2.91-3.03 (2H, m), 3.35(3H, s), 4.40 (2H, s), 5.71 (1H, d, J=7.2 Hz), 6.09 (1H, s), 6.23 (1H,d, J=4.2 Hz), 6.80-6.90 (2H, m), 6.90-6.99 (2H, m), 7.06 (1H, s),7.23-7.31 (2H, m), 7.33-7.42 (2H, m), 8.63 (1H, s).

MS(API): Calculated 680.6. Found 679.3 (M−H).

The binding activity of the test compound to RORγt was measured by atime resolved fluorescence resonance energy transfer method (TR-FRET)utilizing histidine-tagged RORγt, fluorescent-labeled synthetic ligand,and terbium-labeled anti-histidine tag antibody (Invitrogen). First, atest compound diluted with an assay buffer (20 mM Tris-HCl (pH 7.5), 100mM NaCl, 1 mM DTT, 0.1% BSA) was added to a 384 well plate by 3 μL.Then, RORγt diluted with an assay buffer to 240 nM was added by 3 μL,after which fluorescent-labeled synthetic ligand diluted with the assaybuffer to 12 μM was added by 3 μL, and the mixture was stood at roomtemperature for 20 min. Thereafter, a terbium-labeled anti-histidine tagantibody diluted with the assay buffer to 8 nM was added by 3 μL. Themixture was stood at room temperature for 20 min, and fluorescenceintensity (excitation wavelength 320 nm, fluorescence wavelength 520 nm,delay time 100 microseconds) was measured by Envision (PerkinElmer).

The results (binding inhibitory rate of fluorescent-labeled syntheticligand to RORγt at test compound 1 μM) measured by the above-mentionedmethod are shown in Tables 3-1 to 3-2.

Experimental Example 2 Cofactor Recruitment Test

Cofactor recruitment test was performed by Alpha Screen (HistidineDetection Kit, PerkinElmer) method. First, a test compound was dilutedwith an assay buffer (50 mM Tris-HCl (pH 7.5), 50 mM KCl, 1 mM DTT, 0.1%BSA) and added to a 384 well plate by 5 μL. Then, RORγt diluted with anassay buffer to 125 nM was added by 10 μL each, after which solutions of25 nM biotinylated SRC-1 peptide (biotin-CLTARHKILHRLLQEGSPSD), 12.5μg/mL acceptor beads and 12.5 μg/mL donor beads prepared with the assaybuffer were added by 10 μL each. The mixture was stood in a dark placefor 1 hr, and the signal value was measured by Envision (PerkinElmer).

The results (signal value inhibitory rate at test compound 1 μM)measured by the above-mentioned method are shown in Tables 2-1 to 2-6.

Experimental Example 3 Jurkat Reporter Test

The Jurkat cells used for the reporter test were cultured in a culturemedium (RPMI (Invitrogen), 10% FCS (AusGeneX), 100 U/mL penicillin, 100μg/mL streptomycin). On the day of the test, 4×10⁷ cells were recoveredby a centrifugal operation (1000 rpm, 5 min.) and suspended in PBS(phosphate buffered saline) (Invitrogen). Thereafter, the cells wererecovered again by a centrifugal operation, and suspended in 2 mL of Rbuffer (NEON transfection kit, Invitrogen). Then, a reporter vector 53μg wherein a human IL-17 ROR response element was inserted into theupstream of luciferase of pGL 4.28 (Promega), and a vector (27 μg)wherein RORγt sequence was inserted into the downstream of CMV promoterwere added to the cell suspension. Gene transfer was performed byElectroporation apparatus (NEON, Invitrogen) under the conditions ofpulse voltage 1350 V, interval 10 milliseconds, number of times 3. Thecells after gene transfer were suspended in 40 mL of a reaction medium(RPMI, 10% Lipid reduced FCS (HyClone), 10 mM HEPES (pH 7.5), 100 U/mLpenicillin, 100 μg/mL streptomycin, 5 μM lovastatin), and plated in a 96well plate by 90 μL. A test compound diluted with the reaction mediumwas added by 10 μL, and the cells were cultured overnight in anincubator. Bright-Glo (Promega) was added by 100 μL, and the mixture wasstirred at room temperature for 10 min, and the luminescence level wasmeasured by Envision (PerkinElmer).

The results (luminescence level inhibitory rate at test compound 3 μM)measured by the above-mentioned method are shown in Tables 2-1 to 2-6.

TABLE 2-1 Experimental Example 1 Binding inhibitory Experimental rate ofExperimental Example 3 fluorescent- Example 2 Luminescence labeledSignal level 1 cholesterol value inhibitory to RORyt inhibitory rate attest rate at test at test Ex. compound compound compound No. 1 μm (%) 1μm (%) 3 μm (%)  2 99.7 80.5 98.1  3 101 92.7 99.6  4 101 81.9 99.7  7102 92.8 101  8 102 81.2 101  9 100 77.3 101 10 98.9 43.8 93.8 11 10367.7 99.7 12 103 83.4 99.3 13 100 80.4 101 25 102 85.8 102 26 97.7 81.5102 27 103 82.8 101 28 102 83.2 101 29 102 88 102 30 102 82 99.8 32 10189.8 103 36 101 67.1 97.7 37 103 98.3 98.6 41 102 74.9 98.9 43 102 88.3101 45 103 76.9 99.6 54 100 81.9 101 55 102 73.4 100 56 101 61.3 99.9

TABLE 2-2 Experimental Example 1 Binding inhibitory Experimental rate ofExperimental Example 3 fluorescent- Example 2 Luminescence labeledSignal level 1 cholesterol value inhibitory to RORyt inhibitory rate attest rate at test at test Ex. compound compound compound No. 1 μm (%) 1μm (%) 3 μm (%)  63 100 70 99.9  65 102 98 100  66 102 82 99.5  67 10387 100  68 103 73 99  69 102 83 100  70 102 82 99  72 104 94 100  73 10290 100  75 101 78 96  77 101 91 100  78 101 89 101  79 102 97 102  80102 97 100  82 102 98 100  84 101 92 100  85 103 99 101  86 103 98 101 88 102 98 102  92 103 99 102  94 103 99 103  95 102 98 103  97 102 96102  98 99 96 102 101 102 99 103

TABLE 2-3 Experimental Example 1 Binding inhibitory Experimental rate ofExperimental Example 3 fluorescent- Example 2 Luminescence labeledSignal level 1 cholesterol value inhibitory to RORyt inhibitory rate attest rate at test at test Ex. compound compound compound No. 1 μm (%) 1μm (%) 3 μm (%) 103 104 101 102 104 102 101 102 105 103 100 101 106 102101 102 107 103 100 102 109 103 95 102 110 102 100 103 111 103 99 103113 104 99 101 114 103 98 101 115 103 89 102 117 102 87 101 118 104 81100 121 101 100 103 122 102 99 103 124 101 99 102 125 102 99 102 126 101100 102 128 103 100 103 129 98 99 102 130 102 100 104 131 103 100 103132 100 98 104 133 103 96 103 135 102 97 104

TABLE 2-4 Experimental Example 1 Binding inhibitory Experimental rate ofExperimental Example 3 fluorescent- Example 2 Luminescence labeledSignal level 1 cholesterol value inhibitory to RORyt inhibitory rate attest rate at test at test Ex. compound compound compound No. 1 μm (%) 1μm (%) 3 μm (%) 136 100 97 103 137 102 98 103 138 102 100 104 140 100 95102 143 101 56 83 144 101 97 101 145 102 92 100 147 101 89 101 149 10399 103 151 99 99 102 152 102 97 103 153 100 84 97 154 101 85 98 155 10184 99 156 102 98 103 157 99 74 94 158 101 76 93 159 100 80 97 160 100 8298 161 100 76 90 162 99 82 95 163 100 97 101 164 101 96 101 165 101 96101 166 100 86 99

TABLE 2-5 Experimental Example 1 Binding inhibitory Experimental rate ofExperimental Example 3 fluorescent- Example 2 Luminescence labeledSignal level 1 cholesterol value inhibitory to RORyt inhibitory rate attest rate at test at test Ex. compound compound compound No. 1 μm (%) 1μm (%) 3 μm (%) 167 101 85 97 168  97 86 99 169 102 93 102 170 102 81 97171 100 82 96 172 101 82 97 173 101 97 99 174 101 88 98 179 NT 94 102180 NT 93 100 182 NT 67 99 183 NT 91 102 184 NT 93 100 187 NT 93 103 192NT 95 102 194 NT 87 100 195 NT 89 101 196 NT 91 100 209 NT 87 99 210 NT76 98 211 NT 92 101 221 NT 97 101 222 NT 94 100 227 NT 95 101 231 NT 96101

TABLE 2-6 Experimental Example 1 Binding inhibitory Experimental rate ofExperimental Example 3 fluorescent- Example 2 Luminescence labeledSignal level 1 cholesterol value inhibitory to RORyt inhibitory rate attest rate at test at test Ex. compound compound compound No. 1 μm (%) 1μm (%) 3 μm (%) 235 NT 45 93 238 NT 92 100 240 NT 91 101 242 NT 94 101248 NT 87 100 254 NT 101 102 256 NT 102 83 260 NT 95 101 272 NT 101 100273 NT 62 96 279 NT 89 100 281 NT 89 102 282 NT 56 95

TABLE 3-1 Experimental Example 1-2 Binding inhibitory rate offluorescent- labeled synthetic ligand to RORyt at test Ex. compound No.1 μm (%)  7 101  13 102  25 101  26 101  27 101  41 102  43 102  45 102 56 102  63 102  65 101  66 102  67 102  68 101  69 101  70 102  72 102 73 102  75 102  78 102  79 102  80 102  82 102  86 102  88 102  94 101 97 101  98 102 101 102 103 101 104 101 105 101 106 102 107 101 109 102110 102 111 101 114 102 115 101 117 102 118 102 121 101 125 101 126 101129 101 130 101 131 101 132 102 133 101 135 101

TABLE 3-2 Experimental Example 1-2 Binding inhibitory rate offluorescent- labeled synthetic ligand to RORyt at test Ex. compound No.1 μm (%) 136 102 137 102 138 101 140 101 143 101 144 101 147 101 151 102152 101 153 102 154 102 155 101 157 102 159 101 163 102 166 102 167 102169 102 170 102 171 101 172 101 179 101 180 101 182 101 183 101 184 101187 101 192 102 194 101 195 101 196 102 209 102 210 101 211 101 221 102222 102 227 102 231 101 235 102 238 101 240 101 242 101 248 101 254 102256 100 260 102 272 102 273 101 279 102 281 102 282 102

Experimental Example 4 Effect on IL-17 Production in Human Blood

The inhibitory effect of the test compound on IL-17 production in humanblood was evaluated as follows. First, 150 μL of peripheral bloodcollected from healthy individuals using heparinized vacuum bloodcollection tubes was dispensed into each well of a 96-well plate(Corning), and 45 μL of RPMI 1640 medium (Gibco) containing 10% fetalbovine serum (FBS, Hyclone) and 30 μL of the test compound diluted withthe medium was added to each well. The plate was then cultured for 30min at 37° C. Cells were subsequently stimulated by adding 30 μL of 100ng/mL human IL-23 (R&D) and 45 μL of Dynabeads Human (Invitrogen) toeach well and culturing the plate for 3 days at 37° C. In wells withoutstimulation, 75 μL of RPMI 1640 medium containing 10% FBS was addedinstead of the IL-23 and Dynabeads solution. After culturing for 3 days,the culture supernatant was collected, and the amount of IL-17 in thesupernatant was measured using an IL-17 ELISA kit (R&D).

The results of the above-described measurements (percent inhibition ofIL-17 production with 10 μM of the test compound) are shown in Table 4.

TABLE 4 Percent Example Inhibition No. at 10 μM  82 75% 118 88% 140 91%144 86% 179 82% 260 89% 266 88% 272 93% 273 89%

The results above showed that the example compounds inhibited IL-17production in human blood.

Experimental Example 5 Effect on IL-23-Induced Cytokine Expression inMice

A mouse IL-23 solution (500 ng/10 μL, prepared by Takeda PharmaceuticalCompany Limited) or PBS (10 μL, negative control group) was administeredintradermally in the ear of Balb/c mice (Charles River Japan, male, 7weeks old). Twenty-four hr after administration, the ear was resectedunder isoflurane anesthesia. The test compound was suspended in 0.5%methylcellulose and administered orally 30 min before and 8 hr afterIL-23 administration. RNA extraction from the ear tissue andquantitative PCR were performed as follows. Specifically, ear tissue 5mm in diameter was punched from an area of the resected ear centering onthe IL-23 injection site, and the tissue was immersed in RNAlater(QIAGEN) for at least 18 hr. The RNAlater-treated ear tissue washomogenized in 350 μL of RLT buffer (RNeasy mini kit, QIAGEN) andtreated (55° C., 10 min) with Proteinase K (QIAGEN). Total RNA was thenextracted according to the RNeasy mini kit protocol. The RNA thusobtained was then reverse transcribed into cDNA using the High-CapacityRNA-to-cDNA kit (Applied Biosystems), and the amount of each cytokineexpressions was measured by real-time PCR (Viia7™, Applied Biosystems).The PCR buffer used was TaqMan Fast Advanced Master Mix (AppliedBiosystems), and TaqMan Gene Expression Assays (Applied Biosystems)Mm00439618_ml (IL-17A) and 4352341E (3-actin) were used for cytokinegene detection. The IL-17A gene expression level was normalized to theβ-actin gene expression level, and the percent inhibition of IL-17A geneexpression with the test compound was then calculated.

The results obtained with the above-described method (percent inhibitionof IL-17A gene expression with oral administration of the test compound)are shown in Table 5.

TABLE 5 Percent inhibition of IL-17A Example Dose gene No. (mg/kg)expression* 68 100 90% 82 10 85% 109 30 96% 118 10 87% 125 30 89% 135 3068% 140 30 90% 176 30 91% 179 30 95% 260 10 76% 272 10 86% 273 10 77%279 10 71% 281 10 93% *versus the negative control group

The results above showed that oral administration of the examplecompounds inhibited IL-17A gene expression in vivo.

Experimental Example 6 Effect in a Mouse Model of IL-23-InducedPsoriasis

Mouse IL-23 (500 ng/15 μL, R&D) or PBS (15 μL, negative control group)was administered intradermally in the ear of Balb/c mice (Charles RiverJapan, male, 7 weeks old) 5 times every other days. Seven hr after IL-23administration at 8 days after the initial administration (finaladministration), the mice were anesthetized with isoflurane, and earthickness was measured with calipers. After the ear thickness wasmeasured, the ear was resected, tissue 8 mm in diameter was punched froman area centering on the IL-23 injection site, and the tissue wasweighed. The punched ear tissue was cut in half, and one half wasimmersion-fixed in 10% neutral buffer formalin solution for use inhistopathological evaluation. The other half was immersed in RNAlater(QIAGEN) for at least 18 hr for use in an evaluation of the IL-17A mRNAexpression level. The test compound was suspended in 0.5%methylcellulose and administered orally twice daily on consecutive daysfrom 30 min before the initial IL-23 administration to 30 min before thefinal IL-23 administration.

The change in ear thickness in this model was evaluated by calculatingthe difference in measured thickness between before IL-23 administrationand 7 hr after the final IL-23 administration. In addition, theformalin-fixed tissue was embedded and sectioned, then stained withhematoxylin-eosin. The degree of acanthosis was then evaluatedqualitatively by microscopy (classified with a score of 0 to 4). RNAextraction from the ear tissue and quantitative PCR were performed asfollows. As described above, ear tissue treated with RNAlater (QIAGEN)was homogenized in 350 μL of RLT buffer (RNeasy mini kit, QIAGEN) andtreated (55° C., 10 min) with Proteinase K (QIAGEN). Total RNA was thenextracted according to the RNeasy mini kit protocol. The RNA thusobtained was reverse transcribed into cDNA using the High-CapacityRNA-to-cDNA kit (Applied Biosystems), and the expression of each genewas measured by real-time PCR (Viia7™, Applied Biosystems). The PCRbuffer used was TaqMan Fast Advanced Master Mix (Applied Biosystems),and TaqMan Gene Expression Assays (Applied Biosystems) Mm00439618 ml(IL-17A) and 4352341E (R-actin) were used to detect the genes. TheIL-17A gene expression level was normalized to the 3-actin geneexpression level, and the percent inhibition of IL-17A gene expressionwith the test compound was then calculated.

The measurement results obtained with the above-described method (earthickness, acanthosis score, and percent inhibition of IL-17A geneexpression with oral administration of the test compound) are shown inTable 6.

TABLE 6 Percent Percent Inhibition Percent Inhibition of InhibitionExample Dose of Ear Acanthosis of IL-17 A No. (mg/kg) Thickness* Score*Expression* 118 30 61% 80% 111%

The results above showed that oral administration of the examplecompounds inhibited the increase in ear thickness, acanthosis, andIL-17A gene expression in the mouse model of psoriasis.

Formulation Example 1

(1) the compound of Example 1 10.0 g (2) lactose 70.0 g (3) cornstarch50.0 g (4) soluble starch  7.0 g (5) magnesium stearate  3.0 g

The compound of Example 1 (10.0 g) and magnesium stearate (3.0 g) aregranulated in aqueous solution (70 mL) of soluble starch (7.0 g assoluble starch) and then dried, the resulting mixture is mixed withlactose (70.0 g) and cornstarch (50.0 g) (lactose, cornstarch, solublestarch and magnesium stearate are all products in compliance withJapanese Pharmacopoeia 14′ Edition). The mixture compressed to givetablets.

INDUSTRIAL APPLICABILITY

The compound of the present invention has a superior RORγt inhibitoryaction, and useful as an agent for the prophylaxis or treatment ofpsoriasis, inflammatory bowel disease (IBD), ulcerative colitis (UC),Crohn's disease (CD), rheumatoid arthritis, multiple sclerosis, uveitis,asthma, ankylopoietic spondylarthritis, systemic lupus erythematosus(SLE) and the like.

This application is based on patent application No. 2013-140210 filed onJul. 3, 2013 in Japan, the contents of which are encompassed in fullherein.

1. A compound represented by the following formula (I):

wherein Ring A is an optionally further substituted 6-membered aromaticring, R¹ is (1) a group represented by the formula:-Q(R^(1a))(R^(1b))(R^(1c)) wherein Q is a carbon atom, a silicon atom ora germanium atom, and R^(1a), R^(1b) and R^(1c) are each independently asubstituent, or R^(1a) and R^(1b) in combination optionally form,together with the adjacent Q, an optionally further substituted ring,and R^(1c) is optionally bonded to one substituent for Ring A to form anoptionally further substituted ring, (2) a neo-pentyl group, or (3) atrimethylsilylmethyl group, R¹¹ is —CR¹²R^(12′)—R^(12″), —C(═O)—R⁴ or—SO₂—R³, R¹², R^(12′) and R^(12″) are each independently a hydrogenatom, a halogen atom, a cyano group, a nitro group, an optionallysubstituted C₁₋₆ alkyl group, an optionally substituted C₂₋₆ alkenylgroup, an optionally substituted C₂₋₆ alkynyl group, an optionallysubstituted heterocyclic group or an optionally substitutedthiocarbamoyl group, R⁴ is an optionally substituted C₁₋₆ alkyl group,an optionally substituted C₂₋₆ alkenyl group, an optionally substitutedC₂₋₆ alkynyl group, an optionally substituted heterocyclic group, anacyl group, an optionally substituted amino group, an optionallysubstituted carbamoyl group, an optionally substituted thiocarbamoylgroup, an optionally substituted sulfamoyl group, an optionallysubstituted hydroxy group, an optionally substituted sulfanyl(SH) groupor an optionally substituted silyl group, wherein the “C₁₋₆ alkylgroup”, the “C₂₋₆ alkenyl group” and the “C₂₋₆ alkynyl group” of the“optionally substituted C₁₋₆ alkyl group”, the “optionally substitutedC₂₋₆ alkenyl group” and the “optionally substituted C₂₋₆ alkynyl group”for R⁴ are each optionally substituted by 1 to 5 substituents selectedfrom (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) anoxo group, (5) a hydroxy group, (6) a C₁₋₆ alkoxy group optionallysubstituted by substituent(s) selected from a halogen atom and a carboxygroup, (7) a C₆₋₁₄ aryloxy group, (8) a C₇₋₁₆ aralkyloxy group, (9) a 5-to 14-membered aromatic heterocyclyloxy group, (10) a 3- to 14-memberednon-aromatic heterocyclyloxy group, (11) a C₁₋₆ alkyl-carbonyloxy group,(12) a C₆₋₁₄ aryl-carbonyloxy group, (13) a C₁₋₆ alkoxy-carbonyloxygroup, (14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group, (15) a C₆₋₁₄aryl-carbamoyloxy group, (16) a 5- to 14-membered aromaticheterocyclylcarbonyloxy group, (17) a 3- to 14-membered non-aromaticheterocyclylcarbonyloxy group, (18) an optionally halogenated C₁₋₆alkylsulfonyloxy group, (19) a C₆₋₁₄ arylsulfonyloxy group optionallysubstituted by C₁₋₆ alkyl group(s), (20) an optionally halogenated C₁₋₆alkylthio group, (21) a 5- to 14-membered aromatic heterocyclic groupoptionally substituted by substituent(s) selected from a hydroxy group,a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group and a carboxy group, (22) a 3-to 14-membered non-aromatic heterocyclic group optionally substituted bysubstituent(s) selected from an oxo group and a C₁₋₆ alkyl group, (23) aformyl group, (24) a carboxy group, (25) an optionally halogenated C₁₋₆alkyl-carbonyl group, (26) a C₆₋₁₄ aryl-carbonyl group, (27) a 5- to14-membered aromatic heterocyclylcarbonyl group, (28) a 3- to14-membered non-aromatic heterocyclylcarbonyl group, (29) a C₁₋₆alkoxy-carbonyl group, (30) a C₆₋₁₄ aryloxy-carbonyl group, (31) a C₇₋₁₆aralkyloxy-carbonyl group, (32) a carbamoyl group, (33) a thiocarbamoylgroup, (34) a mono- or di-C₁₋₆ alkyl-carbamoyl group, (35) a C₆₋₁₄aryl-carbamoyl group, (36) a 5- to 14-membered aromaticheterocyclylcarbamoyl group, (37) a 3- to 14-membered non-aromaticheterocyclylcarbamoyl group, (38) an optionally halogenated C₁₋₆alkylsulfonyl group, (39) a C₆₋₁₄ arylsulfonyl group, (40) a 5- to14-membered aromatic heterocyclylsulfonyl group, (41) an optionallyhalogenated C₁₋₆ alkylsulfinyl group, (42) a C₆₋₁₄ arylsulfinyl group,(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group, (44) anamino group, (45) a mono- or di-C₁₋₆ alkylamino group (the C₁₋₆ alkyl isoptionally substituted by carboxy group(s)), (46) a mono- or di-C₆₋₁₄arylamino group, (47) a 5- to 14-membered aromatic heterocyclylaminogroup, (48) a C₇₋₁₆ aralkylamino group, (49) a formylamino group, (50) aC₁₋₆ alkyl-carbonylamino group, (51) a (C₁₋₆ alkyl) (C₁₋₆alkyl-carbonyl)amino group, (52) a C₆₋₁₄ aryl-carbonylamino group, (53)a C₁₋₆ alkoxy-carbonylamino group, (54) a C₇₋₁₆ aralkyloxy-carbonylaminogroup, (55) a C₁₋₆ alkylsulfonylamino group, (56) a C₆₋₁₄arylsulfonylamino group optionally substituted by C₁₋₆ alkyl group(s),(57) an optionally halogenated C₁₋₆ alkyl group, (58) a C₂₋₆ alkenylgroup, and (59) a C₂₋₆ alkynyl group, R¹³ is a substituent, Ring B is abenzene ring, a pyridine ring or a dihydropyridine ring, each of whichis optionally further substituted, the partial structure represented bythe formula:

is CR^(5a)═CR⁶, CR^(5b)═N or C(═O)—NR⁷, R^(5a) and R^(5b) are eachindependently an optionally substituted alkyl group, an optionallysubstituted alkoxy group, an optionally substituted alkylsulfonyl group,a cyano group, an optionally substituted cyclic amino group or anoxetan-3-yloxy group, and R⁶ and R⁷ are each independently a hydrogenatom or a substituent, or the substituent that Ring B optionally furtherhas and R^(5a) or R^(5b) in combination optionally form Ring D, whereinRing D is a 5- or 6-membered oxygen-containing heterocycle containing 1to 2 oxygen atoms as heteroatoms in addition to carbon atoms, and isfused at the ring forming position, or R^(5a) and R⁶ in combinationoptionally form Ring D′, wherein Ring D′ is a 5- or 6-memberedoxygen-containing heterocycle containing 1 to 2 oxygen atoms asheteroatoms in addition to carbon atoms, and is fused at the ringforming position, Y is an optionally substituted methylene group or anoxygen atom, and W is an optionally substituted C₁₋₂ alkylene group, ora salt thereof.
 2. The compound or salt of claim 1, wherein R¹ is atrimethylsilyl group, an ethyldimethylsilyl group or an optionallysubstituted tert-butyl group, or a group represented by the formula:—C(R^(1a))(R^(1b))(R^(1c)) wherein R^(1a) and R^(1b) are eachindependently a substituent, or R^(1a) and R^(1b) in combinationoptionally form, together with the adjacent carbon atom, an optionallyfurther substituted ring, and R^(1c) is bonded to one substituent forRing A to form an optionally further substituted ring.
 3. The compoundor salt of claim 1, wherein Ring A is a benzene ring optionally furthersubstituted by a halogen atom or a cyano group.
 4. The compound or saltof claim 1, wherein R⁴ is (1) a C₁₋₆ alkyl group optionally substitutedby 1 to 3 substituents selected from (a) a halogen atom, (b) a cyanogroup, (c) a hydroxy group, (d) a 5- to 6-membered monocyclic aromaticheterocyclic group, (e) a 4- to 6-membered monocyclic non-aromaticheterocyclic group, and (f) a carboxy group, or (2) an optionallysubstituted heterocyclic group.
 5. The compound or salt of claim 1,wherein Ring D′ is a dioxole ring.
 6. The compound or salt of claim 1,wherein Y and W are both methylene groups.
 7. The compound or salt ofclaim 1, wherein R^(5a) is (1) an optionally substituted C₁₋₆ alkylgroup, (2) an optionally substituted C₁₋₆ alkoxy group, or (3) anoptionally substituted C₁₋₆ alkylsulfonyl group.
 8. The compound or saltof claim 1, wherein R^(5b) is (1) an optionally substituted C₁₋₄ alkoxygroup, or (2) an optionally substituted C₁₋₄ alkyl group.
 9. Thecompound or salt of claim 1, wherein R⁶ is a hydrogen atom.
 10. Thecompound or salt of claim 1, wherein Ring B is a benzene ring or apyridine ring, each of which is optionally further substituted. 11.5-((5R)-5-((7-Fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-oxopentanoicacid or a salt thereof. 12.(1-(((6R)-6-((3,5-Difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-8,9-dihydro[1,3]dioxolo[4,5-f]isoquinolin-7(6H)-yl)carbonyl)azetidin-3-yl)aceticacid or a salt thereof. 13.(1-(((5R)-5-((3,5-Difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)azetidin-3-yl)aceticacid or a salt thereof.
 14. A medicament comprising the compound or saltof claim
 1. 15. The medicament of claim 14, which is a RORγt inhibitor.16. The medicament of claim 14, which is an agent for the prophylaxis ortreatment of psoriasis, inflammatory bowel disease (IBD), ulcerativecolitis (UC), Crohn's disease (CD), rheumatoid arthritis, multiplesclerosis, uveitis, asthma, ankylopoietic spondylarthritis or systemiclupus erythematosus (SLE).
 17. A method of inhibiting RORγt, whichcomprises administering an effective amount of the compound or salt ofclaim 1 to a mammal.
 18. A method for the prophylaxis or treatment ofpsoriasis, inflammatory bowel disease (IBD), ulcerative colitis (UC),Crohn's disease (CD), rheumatoid arthritis, multiple sclerosis, uveitis,asthma, ankylopoietic spondylarthritis or systemic lupus erythematosus(SLE), which comprises administering an effective amount of the compoundor salt of claim 1 to a mammal.
 19. Use of the compound or salt of claim1 for the production of an agent for the prophylaxis or treatment ofpsoriasis, inflammatory bowel disease (IBD), ulcerative colitis (UC),Crohn's disease (CD), rheumatoid arthritis, multiple sclerosis, uveitis,asthma, ankylopoietic spondylarthritis or systemic lupus erythematosus(SLE).
 20. The compound or salt of claim 1 for use in the prophylaxis ortreatment of psoriasis, inflammatory bowel disease (IBD), ulcerativecolitis (UC), Crohn's disease (CD), rheumatoid arthritis, multiplesclerosis, uveitis, asthma, ankylopoietic spondylarthritis or systemiclupus erythematosus (SLE).